rs193922727
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_000335.5(SCN5A):c.630G>A(p.Val210Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000854 in 1,609,044 control chromosomes in the GnomAD database, including 4 homozygotes. 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 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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SCN5A | ENST00000423572.7 | c.630G>A | p.Val210Val | synonymous_variant | Exon 6 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 | ||
SCN5A | ENST00000413689.6 | c.703+159G>A | intron_variant | Intron 6 of 27 | 5 | NM_001099404.2 | ENSP00000410257.1 |
Frequencies
GnomAD3 genomes AF: 0.000605 AC: 92AN: 152054Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000552 AC: 133AN: 240958Hom.: 0 AF XY: 0.000606 AC XY: 79AN XY: 130468
GnomAD4 exome AF: 0.000880 AC: 1282AN: 1456872Hom.: 4 Cov.: 30 AF XY: 0.000892 AC XY: 646AN XY: 724240
GnomAD4 genome AF: 0.000605 AC: 92AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.000632 AC XY: 47AN XY: 74390
ClinVar
Submissions by phenotype
not provided Benign:6
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not specified Benign:3
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
p.Val210Val in exon 6 of SCN5A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (42/41192) of European chromosomes from by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org/; dbSNP rs193922727). -
Brugada syndrome 1 Uncertain:2
We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38613816-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.000605048 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.27; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as VUS using these collective data. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Cardiomyopathy Benign:2
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Cardiac arrhythmia Benign:2
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Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Dilated cardiomyopathy 1E Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Sick sinus syndrome 1 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Progressive familial heart block, type 1A Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Long QT syndrome 3 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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