Variant 3-38550521-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.11744812).

BP6

Variant 3-38550521-C-T is Benign according to our data. Variant chr3-38550521-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68014.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=3, not_provided=1}. Variant chr3-38550521-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000591 (9/152342) while in subpopulation EAS AF= 0.00116 (6/5178). AF 95% confidence interval is 0.000505. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.5851G>A	p.Val1951Met	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.5848G>A	p.Val1950Met	missense_variant	Exon 28 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.5851G>A	p.Val1951Met	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.5848G>A	p.Val1950Met	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

9

AN:

152224

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000973

AC:

24

AN:

246710

Hom.:

0

AF XY:

0.000134

AC XY:

18

AN XY:

133972

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000674

Gnomad SAS exome

AF:

0.000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000473

AC:

69

AN:

1459326

Hom.:

1

Cov.:

31

AF XY:

0.0000579

AC XY:

42

AN XY:

725560

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000530

Gnomad4 SAS exome

AF:

0.000395

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000901

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

9

AN:

152342

Hom.:

0

Cov.:

33

AF XY:

0.0000671

AC XY:

5

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000195

Hom.:

0

ExAC

AF:

0.0000826

AC:

10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2025	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1951 of the SCN5A protein (p.Val1951Met). This variant is present in population databases (rs41315493, gnomAD 0.06%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 18378609, 21321465, 22685113, 28202948). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68014). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 22685113). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2023	Reported in association with atrial fibrillation, Brugada syndrome, and sudden cardiac arrest (Darbar et al., 2008; Olesen et al., 2012; Song et al., 2017; Wang et al., 2022); Identified in a proband with atrial fibrillation and hypertrophic cardiomyopathy (Nakajima et al., 2011); the variant co-segregated with atrial fibrillation in four affected family members but did not co-segregate with an HCM phenotype; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18378609, 21321465, 30203441, 32048431, 28202948, 36354768, 22685113) -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Ventricular fibrillation, paroxysmal familial, type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 16, 2023

- -

Long QT syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 31, 2015

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 17, 2025

Variant summary: SCN5A c.5851G>A (p.Val1951Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.7e-05 in 246710 control chromosomes, predominantly at a frequency of 0.00067 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 27 - fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05). c.5851G>A has been reported in the literature in individuals affected with Cardiomyopathy (example: Darbar_2008, Nakajima_2011, Olesen_2012, Song_2017). This included a family for which all individuals affected with atrial fibrillation (n=7) were determined to have the variant while all unaffected individuals did not; this providing evidence of the variant co-segregating with disease (Darbar_2008). A functional study, Olesen_2012, found the variant to be associated with decreased fast inactivation and positive voltage shift in recovery from inactivation. The following publications have been ascertained in the context of this evaluation (PMID: 18378609, 22685113, 21321465, 28202948, 30203441, 32048431, 36129056). ClinVar contains an entry for this variant (Variation ID: 68014). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Dilated cardiomyopathy 1E

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Sick sinus syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Progressive familial heart block, type 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Long QT syndrome 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

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. -

Cardiac arrhythmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 06, 2018

- -

Atrial fibrillation

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609;PMID:21321465;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

CardioboostCm

Benign

0.0085

BayesDel_addAF

Benign

-0.094

T

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

0.42

DANN

Benign

0.62

DEOGEN2

Benign

0.34

.;.;.;.;.;T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.049

N

LIST_S2

Benign

0.46

.;T;T;T;T;T;T;.;T

M_CAP

Uncertain

0.20

D

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.41

T

MutationAssessor

Benign

-2.5

.;.;.;.;.;N;.;.;.

PrimateAI

Benign

0.30

T

PROVEAN

Benign

1.4

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.64

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;.;B;B;.;.

Vest4

0.66

MutPred

0.74

.;.;Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);.;.;.;

MVP

0.98

MPC

0.51

ClinPred

0.015

T

GERP RS

-0.53

Varity_R

0.030

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

3-38550521-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over