rs199473600
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2PP2BP4BP6BS1
The NM_000335.5(SCN5A):c.3748G>A(p.Val1250Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SCN5A | NM_001099404.2 | c.3751G>A | p.Val1251Met | missense_variant | Exon 21 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.3748G>A | p.Val1250Met | missense_variant | Exon 21 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3751G>A | p.Val1251Met | missense_variant | Exon 21 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.3748G>A | p.Val1250Met | missense_variant | Exon 21 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.000368 AC: 56AN: 152118Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000199 AC: 50AN: 251448Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135898
GnomAD4 exome AF: 0.0000643 AC: 94AN: 1461770Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44AN XY: 727192
GnomAD4 genome AF: 0.000368 AC: 56AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24AN XY: 74428
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4Other:1
This variant is associated with the following publications: (PMID: 19841300, 20129283, 15851227, 26746457, 25904541) -
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This variant has been reported in the following publications (PMID:19841300;PMID:20129283). -
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not specified Uncertain:1Benign:1
Variant classified as Uncertain Significance - Favor Benign. The p.Val1251Met va riant in SCN5A has not been reported in any other families with DCM. However, it has been identified in a cohort of apparently unaffected African American indiv iduals (1/736 chromosomes; Kapa 2009), as well as in 0.2% (20/10346) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs199473600). Computational prediction tools and conservation analy sis do not provide strong support for or against an impact to the protein. In su mmary, while the clinical significance of the p.Val1251Met variant is uncertain, its frequency suggests that it is more likely to be benign. -
Variant summary: SCN5A c.3751G>A (p.Val1251Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251448 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.3751G>A has been reported in the literature (example Kapa_2009. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia/Brugada/Long QT syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a high throughput patch clamp assay that resulted in re-classification of this variant as benign in accordance with the ACMG classification criteria (example, Glazer_2020). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as benign. -
Cardiac arrhythmia Benign:2
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at