Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006231.4 | MANE Select | 7823 nt | 28–6888 |
| NM_006231.2 | Alternative | 7859 nt | 45–6905 |
| NM_006231.3 | RefSeq Select | 8024 nt | 210–7070 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (6 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 147 bp |
| Donor Loss (DL) | 0.0 | -199 bp |
| Acceptor Gain (AG) | 0.0 | -96 bp |
| Donor Gain (DG) | 0.0 | 68 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule definition for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: it is a deep intronic change (c.720+16T>C) outside the canonical splice sites and does not introduce a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not predicted to result in loss of function.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule definition for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: it is an intronic variant with no amino acid change. Therefore, this criterion is not applied at Not Applied strength because there is no amino acid alteration to compare.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule definition for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied at Not Applied strength due to lack of de novo confirmation.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule definition for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional data are missing.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule definition for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or affected-individual data are available. Therefore, this criterion is not applied at Not Applied strength due to absence of prevalence data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule definition for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: it is a deep intronic variant outside known functional domains. Therefore, this criterion is not applied at Not Applied strength because it is not in a recognized hotspot or domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule definition for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: a minor allele frequency of 0.00637% in gnomAD with no homozygotes, representing extreme rarity. Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule definition for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: no data on phase with other variants are available. Therefore, this criterion is not applied at Not Applied strength because trans status is unknown.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule definition for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is a single-nucleotide intronic change with no effect on protein length. Therefore, this criterion is not applied at Not Applied strength because there is no protein length alteration.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule definition for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: it is intronic with no amino acid change. Therefore, this criterion is not applied at Not Applied strength because no missense residue is involved.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule definition for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied at Not Applied strength because there is no de novo assumption.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule definition for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied at Not Applied strength due to lack of segregation evidence.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule definition for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: it is intronic, not missense. Therefore, this criterion is not applied at Not Applied strength because PP2 requires a missense change.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule definition for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)'. The evidence for this variant shows: in silico predictors (CADD score 0.04, SpliceAI scores all 0) predict no deleterious effect. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support a damaging effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule definition for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype or clinical information is provided. Therefore, this criterion is not applied at Not Applied strength due to missing phenotype data.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule definition for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: reputable sources report it as benign, not pathogenic. Therefore, this criterion is not applied at Not Applied strength because there are no reports of pathogenic classification.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule definition for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: allele frequency is 0.00637%, which is well below thresholds for BA1. Therefore, this criterion is not applied at Not Applied strength because the frequency is not too high.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule definition for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: 0.00637% is not greater than expected. Therefore, this criterion is not applied at Not Applied strength.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule definition for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: presence in population databases without phenotype information does not confirm healthy status. Therefore, this criterion is not applied at Not Applied strength due to lack of confirmed healthy individuals.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule definition for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied at Not Applied strength because functional data are missing.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule definition for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data are provided. Therefore, this criterion is not applied at Not Applied strength due to absence of family data.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule definition for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: it is intronic. Therefore, this criterion is not applied at Not Applied strength because BP1 requires a missense change.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule definition for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no information on cis/trans with other variants. Therefore, this criterion is not applied at Not Applied strength due to missing phase data.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule definition for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: it is a single-nucleotide intronic substitution. Therefore, this criterion is not applied at Not Applied strength because it is not an in-frame indel.
BP4 (Supporting)
According to standard ACMG guidelines, the rule definition for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: CADD score of 0.04 and SpliceAI scores of 0 predict no impact on splicing or function. Therefore, this criterion is applied at Supporting strength because computational predictors uniformly suggest no deleterious effect.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule definition for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no case reports with alternate molecular findings. Therefore, this criterion is not applied at Not Applied strength due to lack of case context.
BP6 (Supporting)
According to standard ACMG guidelines, the rule definition for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: ClinVar entries from six reputable laboratories report it as Likely benign without primary data. Therefore, this criterion is applied at Supporting strength because a reputable source classifies the variant as benign without available supporting evidence.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule definition for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is intronic, not synonymous coding. Therefore, this criterion is not applied at Not Applied strength because BP7 is restricted to synonymous exonic changes.