rs376697724

Variant names:

• chr3-38550365-C-G
• rs376697724
• NM_001099404.2:c.6007G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-38550365-C-G
• chr3-38550365-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000335.5(SCN5A):​c.6004G>C​(p.Asp2002His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,384,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2002N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42287466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.6007G>C	p.Asp2003His	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.6004G>C	p.Asp2002His	missense_variant	Exon 28 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.6007G>C	p.Asp2003His	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.6004G>C	p.Asp2002His	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1384982 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 678632

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31586

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 36178

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 21108

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38902

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 73656

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50558

Gnomad4 NFE exome AF: 0.00000187 AC: 2 AN: 1071004

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 56960

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostArm	Benign	0.0025
CardioboostCm	Benign	0.011
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.55	.;.;.;.;.;N;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;B;D;.;.
Vest4		0.31
MutPred		0.23		.;.;Gain of glycosylation at P2005 (P = 0.0892);.;.;Gain of glycosylation at P2005 (P = 0.0892);.;.;.;
MVP		0.89
MPC		1.6
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.53
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs376697724; hg19: chr3-38591856;