The CFTR NM_000492.4:c.350G>A (NP_000483.3:p.(Arg117His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV50042918, n = 4 times). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be drug response by the VCEP (ClinPGx; ClinVar ID 7109).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.CFTR encodes an ATP-binding cassette family protein that functions as a chloride channel, helping regulate salt and water movement across epithelial tissues. Disruption of CFTR causes cystic fibrosis, an inherited disorder affecting the lungs, digestive system, and other organs; CFTR has no established primary role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met: one affected CBAVD patient had R117H in trans with a maternally inherited complete CFTR-gene deletion, providing direct phase evidence.
Met at moderate strength: missense REVEL 0.807 meets the generic PP3 moderate threshold of >=0.773.
Met: the exact-variant ClinVar expert-panel record from CFTR2 classifies R117H as Pathogenic, satisfying the specified PP5 evidence path.
No benign criterion marked as applied in the recorded assessment.
VUS: PM3 moderate plus PP3 moderate and PP5 supporting do not meet a generic ACMG/AMP pathogenic or likely pathogenic combination.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 3,445 / 1,613,574 alleles. Recorded AF 0.00213501. Recorded homozygote count 6.
This variant is present in gnomAD v2.1 (AF= 0.00143795; MAF= 0.14380%, 406/282346 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00250578; MAF= 0.25058%, 323/128902 alleles, homozygotes = 1); grpmax FAF= 0.00240534.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.807. Refer to the recorded PP3/BP4 rationale for interpretation.
36 Pathogenic · 2 Likely pathogenic · 2 pathogenic · 1 Pathogenic, low penetrance. ClinVar API review status: practice guideline.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV50042918, n = 4 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 5 not met · 16 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Neither PS3 nor BS3 is assessed because the available variant-specific functional evidence is not auditable enough to establish damaging or non-damaging effect strength under generic ACMG/AMP criteria.
PS4 and PP4 cannot be assessed because the required case-control or patient-specific phenotype information is unavailable.
PP5 is met solely from the exact-variant ClinVar expert-panel Pathogenic classification specified for this group.
BP5 lacks a documented alternate molecular basis, and BP6 lacks an exact-variant expert-panel benign classification.
PP3 is met at moderate strength from the applicable missense REVEL path (0.807 >= 0.773).
BP4 is not met because the applicable missense REVEL score (0.807) is above the supporting BP4 cutoff (<= 0.29); SpliceAI and BayesDel do not alter this determination.
Population evidence does not support BA1, BS1, or PM2 because the required filtering frequencies are below the benign/pathogenic thresholds but above the PM2 threshold.
BS2 is not assessed because homozygote counts alone do not document healthy adults or full early-age penetrance, particularly for this low-penetrance CFTR-related allele.
No criteria match.
PM3 is met for this CFTR missense variant. CFTR-related cystic fibrosis and CBAVD are recessive disorders. In a CBAVD patient, the paper reports R117H with IVS8(T)7 in cis and a complete CFTR-gene deletion inherited from the mother; therefore the complete deletion was on the opposite chromosome, in trans to R117H. The patient was affected with CBAVD, and a complete CFTR-gene deletion is a pathogenic loss-of-function allele in this recessive CFTR disorder. This is direct phase and affected-proband evidence for R117H in trans with a pathogenic CFTR allele.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The variant is a missense substitution, NP_000483.3:p.(Arg117His), so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3 in this situation. REVEL is 0.807, meeting the supplied generic ClinGen SVI moderate PP3 threshold of >= 0.773 (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established. The criterion is therefore met at moderate strength without double-counting splice prediction evidence.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only.
The governing rule is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The exact-variant ClinVar submission audit matches the queried CFTR variant and records CFTR2 as an expert-panel submitter with classification Pathogenic, reviewed by expert panel, for cystic fibrosis. Under the specified generic PP5 rule, this exact-variant expert-panel pathogenic classification supports PP5; ordinary laboratory submissions and aggregate labels were not used.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
The queried variant is CFTR NP_000483.3:p.(Arg117His), caused by NM_000492.4:c.350G>A. The supplied evidence establishes this exact R117H variant, but does not establish a previously pathogenic Arg117His substitution caused by a different nucleotide change. The PS1 definition requires the same amino-acid change as a previously established pathogenic variant regardless of nucleotide change; evidence for the same nucleotide-level variant does not satisfy that distinct-nucleotide requirement.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PM2 is not met under the supplied generic supporting threshold. The variant is present above 0.0001 in every relevant large population dataset: gnomAD v4.1 all-comers AF=0.00213501 with 3445/1613574 alleles, gnomAD v2.1 non-cancer exomes AF=0.00142114 with 336/236430 alleles, and gnomAD v3.1 non-cancer genomes AF=0.00150085 with 222/147916 alleles. Although the variant is uncommon, these observations are not absent or at the required extremely low frequency.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
BS1 is not met. Using the required filtering allele frequency rather than the popmax point estimate, gnomAD v4.1 has grpmax FAF=0.00263119 and gnomAD v2.1 non-cancer exomes have grpmax FAF=0.00232094; both are below the generic 0.01 default. The frequency is not confined to a small isolate and no maximum-credible-frequency calculation is needed to reject this default threshold. The observed frequencies therefore do not establish an allele frequency greater than expected for CFTR-related disease under the supplied generic rule.
Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BP2 is not met. The relevant cis observation is R117H with IVS8(T)5/(TG)m(T)5 alleles, but the study explicitly categorizes IVS8(T)5 among mild CFTR defects not currently considered CF-causing, so it is not established as a pathogenic variant for BP2. The paper does not provide a qualifying observation of R117H in cis with another pathogenic variant. The alternative BP2 branch concerns a pathogenic variant in trans in a fully penetrant dominant disorder, whereas CFTR-related cystic fibrosis is recessive.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The variant is a missense substitution, so BP4 must be judged on the REVEL path only; the SpliceAI result cannot substitute for a gray-zone REVEL result. REVEL is 0.807, which is above the supplied generic BP4 supporting cutoff of <= 0.29 and therefore does not support no impact. BayesDel is not used because no generic ACMG-strength calibration is established. BP4 is not met.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only.
The available evidence does not document a de novo occurrence of NM_000492.4:c.350G>A (p.Arg117His) in a patient with confirmed disease and no family history. PMID:17329263 reports R117H in a cohort of 222 unrelated men with isolated congenital bilateral absence of the vas deferens, including 25 R117H alleles, but it does not provide maternity and paternity confirmation for a qualifying patient or establish the required no-family-history context. ClinVar submission metadata listing maternal origin is not parental testing evidence and does not establish de novo status.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The available variant-specific lead identifies a 1993 CFTR functional study as reporting reduced conductance for R117H, but the supplied evidence is only an unverified classifier summary and does not provide auditable assay controls, replication, quantitative results, or diagnostic-laboratory validation. The extracted full-text evidence for PMID:23974870 describes CFTR functional assays but does not explicitly mention R117H, so its aggregate findings cannot be assigned to this variant. The evidence is therefore insufficient to establish the well-established, reproducible functional evidence required for PS3 or to calibrate a PS3 strength.
PS3
The governing rule requires a case-control comparison: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." The supplied literature includes a CBAVD cohort reporting CFTR R117H in 25 of 390 identified alleles, but no unaffected or population-control count from the same study is reported, so a valid case-control odds ratio and 95% confidence interval cannot be computed. The matched-ancestry gnomAD frequency is available (gnomAD v4.1 European non-Finnish AF 0.00270988), but the affected-case denominator and allele frequency for the relevant disease cohort are not available in the cited evidence, so no case-frequency-versus-gnomAD OR can be calculated. The literature_pass PS4 index entries 27364092 and 30279124 are not present as papers in the packet or source registry, and the packet's ai_classified_papers contains only PMID:7680769 classified for PS3, not PS4; therefore no qualifying PS4 evidence is established.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The queried residue is Arg117 in CFTR. The authoritative vcep_materials.json domain_tables entry is empty because no CFTR VCEP material was retrieved. Cancer Hotspots reports no statistically significant hotspot for CFTR R117, and COSMIC reports the exact variant four times in somatic cancers but the generic rule does not establish that this is a mutational hotspot or critical functional domain. The available paper extract describes CFTR as a chloride channel but does not establish residue 117 as a critical, well-established domain lacking benign variation. Therefore the supplied evidence is insufficient to assess PM1.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The variant is p.Arg117His, but the supplied PM5 comparator file contains zero same-residue candidates and no confirmed pathogenic alternate missense change at Arg117. The literature extract available for this case reports R117H itself, not a different missense substitution at residue 117, and the paper titled with R117C is not available in the local publications directory or paper extracts. Thus a qualifying previously pathogenic alternate missense change cannot be verified from the supplied evidence.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available evidence does not document an assumed de novo occurrence of NM_000492.4:c.350G>A (p.Arg117His). PMID:17329263 reports R117H in a CBAVD cohort but does not state that the variant was absent from either parent, and no qualifying proband-level de novo observation is provided. The isolated ClinVar maternal-origin metadata does not supply the required evidence for an assumed de novo event.
Assumed de novo, but without confirmation of paternity and maternity.
No qualifying cosegregation dataset is available for NM_000492.4:c.350G>A. PMID:17329263 reports R117H in unrelated CBAVD patients and describes several R117H-containing genotypes, but it does not report multiple affected family members with genotype and phenotype results across informative meioses. Therefore, the evidence cannot establish cosegregation or justify a PP1 strength.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The queried variant is missense, and the supplied sources document CFTR missense variants including R117H, but they do not provide a gene-level assessment that CFTR has a low rate of benign missense variation together with missense variants being a common disease mechanism under the generic PP2 definition. Variant-level pathogenic submissions and a single cohort cannot establish both gene-level requirements.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing rule is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The case evidence does not provide a phenotype or family-history description for the individual being interpreted, and the available R117H literature describes cohorts rather than this patient's phenotype. Therefore specificity of the patient's presentation for cystic fibrosis or another single CFTR-related disease etiology cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BA1 is not assessed. The relevant filtering frequency is the gnomAD v4.1 grpmax FAF of 0.00263119 (0.263119%), well below the generic stand-alone threshold of 0.05, so frequency alone does not meet BA1. In addition, this CFTR p.Arg117His variant has a strong pathogenic ClinVar consensus, including a low-penetrance designation, and the prompt requires withholding a stand-alone benign call when high frequency and a documented disease association disagree. The gnomAD v2.1 non-cancer exome grpmax FAF is likewise only 0.00232094 and does not change this conclusion.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS2 is not assessed. gnomAD reports homozygotes (1 in gnomAD v2.1 non-cancer exomes, 1 in gnomAD v2.1 overall, 1 in gnomAD v3.1 non-cancer genomes, and 6 in gnomAD v4.1), but these aggregate population records do not establish that the individuals were healthy adults, nor do they document phenotype, age, or the relevant CFTR genotype context. The rule requires observation in a healthy adult with full penetrance expected at an early age; that requirement is especially unresolved for p.Arg117His, which has a documented low-penetrance and variable CFTR-related disease association.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No variant-specific study in the auditable evidence establishes that CFTR p.(Arg117His) has no damaging effect on protein function or splicing. The available PMID:23974870 functional dataset does not explicitly name R117H, and the separate R117H assay lead lacks verified controls, quantitative results, replication, and validation details. Neutral functional evidence sufficient for BS3 strength calibration is therefore unavailable.
BS3
No affected family members with documented negative testing for NM_000492.4:c.350G>A are reported. PMID:17329263 describes unrelated CBAVD patients and does not provide a family-based non-segregation analysis. Consequently, lack of segregation in affected relatives cannot be established, and the phenocopy caveat cannot be evaluated.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals.
The queried variant is missense. The supplied evidence does not establish that CFTR disease is caused primarily by truncating variants, nor does it provide a gene-level comparison showing that missense variants are an uncommon disease mechanism. The existence of reported CFTR missense disease variants is not sufficient by itself to quantify the word primarily in the BP1 definition.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The governing rule is: "Variant found in a case with an alternate molecular basis for disease." The available evidence does not document the interpreted patient's case, an alternate molecular diagnosis, or a case in which this exact CFTR variant was present but another molecular basis explained the disease. Cohort observations of R117H and the general ClinVar pathogenic classification do not establish BP5.
Variant found in a case with an alternate molecular basis for disease.
The governing rule is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The exact-variant ClinVar expert-panel record is Pathogenic, not Benign or Likely benign, and no exact-variant ClinVar expert-panel benign classification is documented. Therefore the specified BP6 trigger is absent.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000492.4:c.350G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Arg117His). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000492.4:c.350G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Arg117His). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000492.4:c.350G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Arg117His). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000492.4:c.350G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Arg117His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in CFTR, mapped onto the exon structure of NM_000492.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)3197 / 1,179,756 | 0.00275 hom |
| European (Finnish)95 / 64,014 | 0.0015 |
| Remaining individuals74 / 62,470 | 0.00121 hom |
| Admixed American37 / 59,904 | 0.00062 |
| African/African American39 / 74,914 | 0.00052 |
| Ashkenazi Jewish3 / 29,596 | 0.0001 |
| European (non-Finnish)323 / 128,902 | 0.00251 hom |
| European (Finnish)44 / 25,092 | 0.0018 |
| Admixed American23 / 35,296 | 0.00065 |
| Remaining individuals4 / 7,204 | 0.00056 |
| African/African American12 / 24,960 | 0.00048 |
This variant is present in gnomAD v4.1 (AF= 0.00213501; MAF= 0.21350%, 3445/1613574 alleles, homozygotes = 6) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00270988; MAF= 0.27099%, 3197/1179756 alleles, homozygotes = 5); grpmax FAF= 0.00263119.
This variant is present in gnomAD v2.1 (AF= 0.00143795; MAF= 0.14380%, 406/282346 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00250578; MAF= 0.25058%, 323/128902 alleles, homozygotes = 1); grpmax FAF= 0.00240534.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NP_000483.3:p.(Arg117His), so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3 in this situation. REVEL is 0.807, meeting the supplied generic ClinGen SVI moderate PP3 threshold of >= 0.773 (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established. The criterion is therefore met at moderate strength without double-counting splice prediction evidence.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only.
The variant is a missense substitution, so BP4 must be judged on the REVEL path only; the SpliceAI result cannot substitute for a gray-zone REVEL result. REVEL is 0.807, which is above the supplied generic BP4 supporting cutoff of <= 0.29 and therefore does not support no impact. BayesDel is not used because no generic ACMG-strength calibration is established. BP4 is not met.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000492.4:c.350G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Arg117His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.807. BayesDel score = 0.410121.
8 paper records listed. 1 cited in the classification.
R117H 25 6.4
Location Table I; Results, paragraph beginning "Sixty-one patients were then investigated for the presence of large rearrangements"
Context Cohort of 222 unrelated infertile patients with isolated congenital bilateral absence of the vas deferens; CFTR exons and splice boundaries were screened by mutation panels, DGGE or DHPLC followed by sequencing, with selected patients evaluated for large rearrangements.
The CFTR protein is a glycosylated transmembrane protein that functions as a chloride channel.
CFTR Gene Mutations and Polymorphisms, page 506
Forty-three variants (41 missense and two in-frame deletions) conducted chloride at a level less than 10% of WT-CFTR and were deemed disease-causing (Figure 3). CFTR bearing each of the remaining 20 missense changes generated chloride conductance that ranged from 10.5% to 147% of WT-CFTR.
Results, Functional analysis, paragraph describing missense and in-frame variants
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00213501; MAF= 0.21350%, 3445/1613574 alleles, homozygotes = 6) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00270988; MAF= 0.27099%, 3197/1179756 alleles, homozygotes = 5); grpmax FAF= 0.00263119.
This variant is present in gnomAD v2.1 (AF= 0.00143795; MAF= 0.14380%, 406/282346 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00250578; MAF= 0.25058%, 323/128902 alleles, homozygotes = 1); grpmax FAF= 0.00240534.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (36 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as pathogenic (2 clinical laboratories) and as Pathogenic, low penetrance (1 clinical laboratory) and as drug response by ClinPGx (expert panel). (ClinVarID = 7109)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.807. BayesDel score = 0.410121.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50042918, n = 4 times).
This variant does not lie in a statistically significant hotspot.