rs12720452

Variant names:

• chr3-38603758-C-G
• NM_001099404.2:c.1844G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-38603758-C-G
• chr3-38603758-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_000335.5(SCN5A):​c.1844G>C​(p.Gly615Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. G615E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38603758-C-T is described in Lovd as [Pathogenic].
• 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=0.10316634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1844G>C	p.Gly615Ala	missense_variant	Exon 12 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1844G>C	p.Gly615Ala	missense_variant	Exon 12 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1844G>C	p.Gly615Ala	missense_variant	Exon 12 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1844G>C	p.Gly615Ala	missense_variant	Exon 12 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
CardioboostCm	Benign	0.0025
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.75	.;T;T;T;T;T;T;.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.1	.;L;.;.;.;L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.92	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.34	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T;T;T;T;T
Polyphen		0.0050	B;B;.;B;.;B;B;.;.
Vest4		0.15
MutPred		0.24		Gain of glycosylation at P614 (P = 0.1711);Gain of glycosylation at P614 (P = 0.1711);Gain of glycosylation at P614 (P = 0.1711);Gain of glycosylation at P614 (P = 0.1711);Gain of glycosylation at P614 (P = 0.1711);Gain of glycosylation at P614 (P = 0.1711);Gain of glycosylation at P614 (P = 0.1711);Gain of glycosylation at P614 (P = 0.1711);Gain of glycosylation at P614 (P = 0.1711);
MVP		0.81
MPC		0.56
ClinPred		0.21	T
GERP RS		4.2
Varity_R		0.10
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-38645249;