The APOE NM_000041.4:c.526C>T (NP_000032.1:p.(Arg176Cys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV52986153, n = 8 times). Based on available guidelines, this variant is considered to be Benign. This variant is considered to be drug response by the VCEP (ClinPGx; ClinVar ID 17848).
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.APOE encodes apolipoprotein E, which helps the liver and other cells clear triglyceride-rich lipoprotein remnants from the blood. Changes in this gene can cause familial dysbetalipoproteinemia (type III hyperlipoproteinemia), leading to increased cholesterol and triglyceride levels. APOE has no established cancer role based on the available information.
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.
No pathogenic criterion marked as applied in the recorded assessment.
Met: gnomAD grpmax FAF is 10.14% in v2.1 and 10.36% in v4.1, exceeding the 5% generic BA1 threshold with adequate observed-allele counts.
Benign: BA1 (stand-alone benign) is met because gnomAD grpmax filtering allele frequencies exceed 5%, satisfying the generic ACMG/AMP 2015 fallback rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 114,390 / 1,540,810 alleles. Recorded AF 0.0742402. Recorded homozygote count 4609.
This variant is present in gnomAD v2.1 (AF= 0.065422; MAF= 6.54220%, 10996/168078 alleles, homozygotes = 465) and has highest observed frequency in the African/African American population (AF= 0.106918; MAF= 10.69182%, 1632/15264 alleles, homozygotes = 100); grpmax FAF= 0.101387.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.588. Refer to the recorded PP3/BP4 rationale for interpretation.
4 Likely benign · 2 Benign · 1 risk factor · 1 Uncertain significance · 1 other. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV52986153, n = 8 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: 1 met · 9 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For APOE p.Arg176Cys, PS1, PM1, and PP2 are not met because the variant is a common missense polymorphism without a qualifying established pathogenic same-amino-acid record, hotspot, critical-domain evidence, or low-benign-missense gene context.
PM5 and BP1 remain not assessed because the supplied evidence does not establish a qualifying different pathogenic missense variant at Arg176 or a primarily truncating APOE disease mechanism.
No proband-parent testing, family history, affected-relative genotypes, or informative meioses are documented; therefore PS2, PM6, PP1, and BS4 are not assessed.
BA1 is met from concordant gnomAD grpmax FAF values above 5% with adequate observed-allele counts.
BS1 is not assessed because the case lacks disorder-specific maximum-credible-frequency inputs despite a frequency above the generic 1% default.
BS2 is not assessed because aggregate homozygote counts do not establish healthy-adult status or full early-age penetrance.
PM2 is not met because the variant is common in gnomAD v2.1 and v4.1.
No criteria match.
BA1 is met under the generic ACMG/AMP stand-alone threshold. The variant's filtering allele frequency is 0.101387 in gnomAD v2.1 and 0.103585 in gnomAD v4.1, both above the supplied generic BA1 threshold of 0.05. These are grpmax FAF values, not popmax point estimates, and the corresponding highest-frequency African/African American groups have 15,264 and 73,224 observed alleles, respectively, exceeding the 2,000-observed-allele requirement. No pathogenic ClinVar consensus is documented in this case; ClinVar submissions are benign or likely benign, risk factor, uncertain significance, other, or drug response. The high frequency is therefore not contradicted by a documented pathogenic consensus that would require withholding BA1.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant is APOE p.Arg176Cys (rs7412). The reviewed APOE literature documents this same amino-acid substitution as a common pharmacogenetic polymorphism, not as a previously established pathogenic variant. ClinVar lists four likely-benign and two benign submissions, while its expert-panel classification is drug response rather than pathogenicity. Therefore, no qualifying previously established pathogenic same-amino-acid variant supports PS1.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Generic ACMG/AMP PS4 requires a significant increase of the variant among affected individuals versus controls, with OR or RR >5.0 and a confidence interval excluding 1.0. The reviewed variant-specific papers PMID:16103896 and PMID:19667110 study APOE rs7412/p.Arg176Cys in statin-response cohorts, reporting LDL-cholesterol response differences rather than disease-affected versus unaffected control counts; PMID:17289397 reports APOE genotype groups in statin-treated patients without variant-level case-control enrichment. No paper provides affected/control carrier counts for a disease phenotype, so an OR and 95% CI cannot be computed from these studies. The variant is common in gnomAD v4.1 (AF 0.0742402; 114390/1540810 alleles), which does not establish disease-specific case-control enrichment. The literature_pass ai_classified_papers list is empty, so there were no classifier-designated PS4 papers requiring additional verification.
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.
No VCEP covers APOE, and vcep_materials.json contains no APOE domain table. The supplied evidence does not establish Arg176 as a critical functional domain or mutational hotspot without benign variation: Cancer Hotspots returned no statistically significant hotspot, and the variant is common in gnomAD v4.1 (AF 0.0742402; 4609 homozygotes). The generic PM1 requirement is therefore not met.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is not met because the variant is common in both available default all-comers gnomAD datasets. gnomAD v2.1 reports AF 0.065422 from 10,996 of 168,078 alleles, and gnomAD v4.1 reports AF 0.0742402 from 114,390 of 1,540,810 alleles, with hundreds to thousands of homozygotes. These frequencies are far above the supplied PM2 supporting threshold of <=0.0001. No governing VCEP rule requires a non-cancer or exome-only population source, and no separate non-cancer dataset is present in the case evidence.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
APOE p.Arg176Cys is a frequent missense allele in population data (gnomAD v4.1 AF 0.0742402; 4609 homozygotes), which is inconsistent with a gene having a low rate of benign missense variation. The reviewed APOE literature also describes common missense isoform variation and pharmacogenetic associations rather than establishing the required generic PP2 gene-level pattern. PP2 is not met.
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 variant is missense, APOE NM_000041.4:c.526C>T, p.Arg176Cys, so the generic rule selects the REVEL path only; SpliceAI is not applicable to PP3/BP4 for this missense consequence. The local REVEL score is 0.588, below the supplied generic PP3 supporting threshold of >= 0.644 from the ClinGen SVI calibration by Pejaver et al. 2022 (PMID:36413997), so PP3 is not met. BayesDel is not used because the governing rules state that no generic ACMG-strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
Generic ACMG/AMP PP5 concerns a reputable source reporting the exact variant as pathogenic when the underlying evidence is unavailable for independent evaluation. ClinVar identifies an exact-variant expert-panel classification of drug response, not Pathogenic or Likely pathogenic; the Pathogenic laboratory/literature-only submission was not an expert-panel assertion and was rejected by the submission audit. Therefore the required exact-variant expert-panel pathogenic classification is absent and PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is missense, APOE NM_000041.4:c.526C>T, p.Arg176Cys, so the generic rule selects the REVEL path only; a SpliceAI result cannot support BP4 for this missense variant. The local REVEL score is 0.588, above the supplied generic BP4 supporting threshold of <= 0.29 and therefore in the gray zone; BP4 is not met. BayesDel is not used because the governing rules state that no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
Generic ACMG/AMP BP6 concerns a reputable source reporting the exact variant as benign when the underlying evidence is unavailable for independent evaluation. ClinVar has an exact-variant expert-panel classification of drug response, not Benign or Likely benign. The Benign and Likely benign classifications are ordinary laboratory submissions, so they do not satisfy the required expert-panel exact-variant trigger. BP6 is therefore not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available case evidence does not document a proband with a defined disease phenotype, confirmed maternity and paternity, or absence of family history for APOE NM_000041.4:c.526C>T (p.Arg176Cys). Therefore, the required elements for assessing de novo evidence are not available.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PS3 is not assessed. The reviewed literature includes association studies of the exact APOE rs7412/c.526C>T/p.Arg176Cys variant with statin-related LDL-C response, but these are clinical pharmacogenetic associations rather than validated in vitro or in vivo functional assays. The available assay paper evaluated a different APOE substitution, Arg224Gln, and therefore cannot establish a damaging effect for p.Arg176Cys. No variant-specific, well-established functional assay with appropriate controls and reproducible protein-function or splicing results was identified.
PM3 cannot be assessed because the available evidence does not document an affected proband carrying APOE NM_000041.4:c.526C>T in trans with a pathogenic APOE variant, and no parental or offspring testing establishes phase. The case includes population and pharmacogenetic observations but no compound-heterozygous disease case or phase-confirmed pathogenic allele.
For recessive disorders, detected in trans with a pathogenic variant... This requires testing of parents (or offspring) to determine phase.
The supplied evidence does not establish a different missense substitution at APOE residue Arg176 as pathogenic. The collected PM5 candidate record contains zero same-residue candidates, and the reviewed papers document the tested Arg176Cys polymorphism rather than a different pathogenic missense change at residue 176. A comprehensive residue-level pathogenic-variant search is still required before PM5 can be adjudicated.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available case evidence does not document an assumed de novo occurrence of APOE NM_000041.4:c.526C>T (p.Arg176Cys), nor does it provide the parental or family information needed to distinguish an assumed de novo event from an inherited variant. Therefore, PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, familial genotypes, or meioses demonstrating co-segregation of APOE NM_000041.4:c.526C>T (p.Arg176Cys) with a defined disease are documented. The available publications concern APOE pharmacogenetic or population cohorts rather than familial segregation, so PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Generic ACMG/AMP PP4 requires that the patient's phenotype or family history be highly specific for a disease with a single genetic etiology. The supplied evidence does not provide a patient phenotype or family-history description for this case that can be evaluated against a single-etiology disease, so PP4 cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The observed filtering allele frequencies exceed the supplied generic BS1 default of 0.01: grpmax FAF is 0.101387 in gnomAD v2.1 and 0.103585 in gnomAD v4.1, with adequate observed-allele counts. However, BS1 requires that frequency to be greater than expected for the disorder, and this case provides no defined disorder prevalence, penetrance, allelic heterogeneity, or maximum-credible-frequency calculation. The APOE variant is common and the available case evidence includes risk-factor and benign/likely-benign classifications rather than a defined fully penetrant early-onset disorder; applying the default 1% alone would not satisfy the requested Whiffin-based population-context safeguard. BS1 is therefore not_assessed pending disorder-specific maximum-credible-frequency inputs.
Allele frequency is greater than expected for the disorder.
gnomAD reports 465 homozygotes in v2.1 and 4,609 homozygotes in v4.1, but these aggregate population datasets do not establish that a specific observed homozygote was a healthy adult individual, nor do they establish that the relevant APOE-related disorder has full penetrance expected at an early age. The case evidence also lacks a defined disease/inheritance context for applying the BS2 healthy-adult rule. Homozygote counts alone are therefore insufficient to assess BS2.
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.
BS3 is not assessed. The exact APOE c.526C>T/p.Arg176Cys variant was evaluated in clinical association studies, but those studies did not demonstrate normal protein function or normal splicing. The only detailed functional assay identified in the reviewed papers tested a different APOE Arg224Gln variant, so its preserved receptor binding cannot support BS3 for p.Arg176Cys. No variant-specific, well-established assay showing no damaging effect on protein function or splicing was identified.
No affected family members with documented APOE NM_000041.4:c.526C>T (p.Arg176Cys) genotypes are described, so there are no informative affected-member genotypes from which lack of segregation can be established. The criterion therefore cannot be assessed.
Lack of segregation in affected members of a family.
The supplied evidence does not provide a curated APOE disease-variant spectrum demonstrating that disease is caused primarily by truncating variants. The available APOE literature in this review concerns missense isoforms and pharmacogenetic associations, but it is insufficient to establish the gene-level predominance required for BP1. Therefore BP1 is not assessed.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed because the available evidence does not document APOE c.526C>T in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant. No phase-resolved affected-proband or family data are provided.
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.
Generic ACMG/AMP BP5 requires that the variant be found in a case with an alternate molecular basis for disease. The supplied case evidence does not document a disease case with an established alternate molecular cause, so BP5 cannot be assessed.
Variant found in a case with an alternate molecular basis for disease.
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_000041.4:c.526C>T in APOE is a missense substitution predicted to produce NP_000032.1:p.(Arg176Cys). 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 APOE, 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_000041.4:c.526C>T in APOE is a missense substitution predicted to produce NP_000032.1:p.(Arg176Cys). 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 APOE, 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_000041.4:c.526C>T in APOE is a missense substitution predicted to produce NP_000032.1:p.(Arg176Cys). 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 APOE, 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_000041.4:c.526C>T in APOE is a missense substitution predicted to produce NP_000032.1:p.(Arg176Cys). 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 APOE, 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 APOE, mapped onto the exon structure of NM_000041.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American7729 / 73,224 | 0.11418 hom |
| European (non-Finnish)89919 / 1,148,420 | 0.0783610 hom |
| Ashkenazi Jewish2114 / 28,508 | 0.07484 hom |
| Remaining individuals4221 / 59,868 | 0.071172 hom |
| East Asian2494 / 41,220 | 0.06180 hom |
| Middle Eastern284 / 4,884 | 0.05814 hom |
| European (Finnish)2316 / 48,134 | 0.04877 hom |
| South Asian3511 / 84,314 | 0.042107 hom |
| Admixed American1791 / 51,326 | 0.03547 hom |
| Amish11 / 912 | 0.012 |
| African/African American1632 / 15,264 | 0.11100 hom |
| Ashkenazi Jewish664 / 8,410 | 0.07926 hom |
| European (non-Finnish)5202 / 67,810 | 0.077240 hom |
| East Asian947 / 12,608 | 0.07541 hom |
| Remaining individuals328 / 5,174 | 0.0638 hom |
| European (Finnish)472 / 10,686 | 0.04415 hom |
| South Asian947 / 22,604 | 0.04219 hom |
| Admixed American804 / 25,522 | 0.03216 hom |
This variant is present in gnomAD v4.1 (AF= 0.0742402; MAF= 7.42402%, 114390/1540810 alleles, homozygotes = 4609) and has highest observed frequency in the African/African American population (AF= 0.105553; MAF= 10.55528%, 7729/73224 alleles, homozygotes = 418); grpmax FAF= 0.103585.
This variant is present in gnomAD v2.1 (AF= 0.065422; MAF= 6.54220%, 10996/168078 alleles, homozygotes = 465) and has highest observed frequency in the African/African American population (AF= 0.106918; MAF= 10.69182%, 1632/15264 alleles, homozygotes = 100); grpmax FAF= 0.101387.
Not available in gnomAD-Canada v1.0.
The variant is missense, APOE NM_000041.4:c.526C>T, p.Arg176Cys, so the generic rule selects the REVEL path only; SpliceAI is not applicable to PP3/BP4 for this missense consequence. The local REVEL score is 0.588, below the supplied generic PP3 supporting threshold of >= 0.644 from the ClinGen SVI calibration by Pejaver et al. 2022 (PMID:36413997), so PP3 is not met. BayesDel is not used because the governing rules state that no generic ACMG-strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is missense, APOE NM_000041.4:c.526C>T, p.Arg176Cys, so the generic rule selects the REVEL path only; a SpliceAI result cannot support BP4 for this missense variant. The local REVEL score is 0.588, above the supplied generic BP4 supporting threshold of <= 0.29 and therefore in the gray zone; BP4 is not met. BayesDel is not used because the governing rules state that no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
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_000041.4:c.526C>T in APOE is a missense substitution predicted to produce NP_000032.1:p.(Arg176Cys). 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 APOE, 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 returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.588. BayesDel score = -0.170584.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
The recombinant apo E2 Fukuoka had the same receptor-binding activity as recombinant normal apo E3 on human skin fibroblasts.
Results, section 3.5, Receptor-binding assays; Discussion
Caucasians heterozygous for the rare allele of rs7412 have a 39.9% lowering of LDL-C compared to a 36.4% lowering among Caucasians with the common allele (P = 0.0015).
Results, paragraph beginning “When percent LDL-C lowering by atorvastatin is examined as a function of genotype in Caucasians”; Table 1 and Table 2, rs7412/apoE
The CYP2D6 *1/*4 and *4/4* poor metabolizer (PM) status was associated to a higher efficacy of statins metabolized by this system and, in addition, the apo E2 genotype was, in this series, linked to increased HDL-C levels after therapy.
Abstract; Results section 3.2.4, "Apo E genotype," and Table 4
The defining cSNP for CYP2C9*2 is the 430C3T transition that produces the amino acid change R144C.
Table 3; section “Cytochrome P450 2C9 (OMIM 601130)”
The 2 genetic variants in APOE account for amino acid changes at positions 112 and 158 and haplotype analysis yielded the 3 common isoforms ε2, ε3, and ε4 of apolipoprotein E
Discussion, paragraph describing APOE amino-acid changes and isoforms; Results, APOE subsection
The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose
Introduction, first paragraph
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= 0.0742402; MAF= 7.42402%, 114390/1540810 alleles, homozygotes = 4609) and has highest observed frequency in the African/African American population (AF= 0.105553; MAF= 10.55528%, 7729/73224 alleles, homozygotes = 418); grpmax FAF= 0.103585.
This variant is present in gnomAD v2.1 (AF= 0.065422; MAF= 6.54220%, 10996/168078 alleles, homozygotes = 465) and has highest observed frequency in the African/African American population (AF= 0.106918; MAF= 10.69182%, 1632/15264 alleles, homozygotes = 100); grpmax FAF= 0.101387.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as risk factor (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as other (1 clinical laboratory) and as drug response by ClinPGx (expert panel). (ClinVarID = 17848)
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.588. BayesDel score = -0.170584.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52986153, n = 8 times).
This variant does not lie in a statistically significant hotspot.