3-38603940-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001099404.2(SCN5A):c.1662C>G(p.Ser554Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S554I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.213

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.35322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1662C>G	p.Ser554Arg	missense_variant	12/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1662C>G	p.Ser554Arg	missense_variant	12/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1662C>G	p.Ser554Arg	missense_variant	12/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1662C>G	p.Ser554Arg	missense_variant	12/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 02, 2021

This missense variant replaces serine with arginine at codon 554 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
CardioboostArm	Benign	0.000019
CardioboostCm	Benign	0.0026
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	4.2
Dann	Uncertain	1.0
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.20	N
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	0.83	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.099	T;T;T;T;D;T;T;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T
Polyphen		0.93	P;P;.;P;.;P;P;.;.
Vest4		0.51
MutPred		0.25		Loss of phosphorylation at S554 (P = 0.0241);Loss of phosphorylation at S554 (P = 0.0241);Loss of phosphorylation at S554 (P = 0.0241);Loss of phosphorylation at S554 (P = 0.0241);Loss of phosphorylation at S554 (P = 0.0241);Loss of phosphorylation at S554 (P = 0.0241);Loss of phosphorylation at S554 (P = 0.0241);Loss of phosphorylation at S554 (P = 0.0241);Loss of phosphorylation at S554 (P = 0.0241);
MVP		0.67
MPC		1.2
ClinPred		0.80	D
GERP RS		-2.7
Varity_R		0.11
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-38645431;