3-38598928-G-C

Position:

• chr3-38598928-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000335.5(SCN5A):​c.2013C>G​(p.Ser671Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.434

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

SCN5A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2013C>G	p.Ser671Arg	missense_variant	13/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2013C>G	p.Ser671Arg	missense_variant	13/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2013C>G	p.Ser671Arg	missense_variant	13/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2013C>G	p.Ser671Arg	missense_variant	13/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 671 of the SCN5A protein (p.Ser671Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
CardioboostCm	Benign	0.018
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	9.6
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.9	.;L;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	D;D;D;D;N;D;D;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.50	T;T;T;T;T;T;T;T;T
Polyphen		0.31	B;D;.;B;.;P;P;.;.
Vest4		0.58
MutPred		0.27		Loss of glycosylation at S671 (P = 0.0342);Loss of glycosylation at S671 (P = 0.0342);Loss of glycosylation at S671 (P = 0.0342);Loss of glycosylation at S671 (P = 0.0342);Loss of glycosylation at S671 (P = 0.0342);Loss of glycosylation at S671 (P = 0.0342);Loss of glycosylation at S671 (P = 0.0342);Loss of glycosylation at S671 (P = 0.0342);Loss of glycosylation at S671 (P = 0.0342);
MVP		0.86
MPC		0.76
ClinPred		0.98	D
GERP RS		-2.5
Varity_R		0.45
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs751050999; hg19: chr3-38640419;