rs771018427

chr3-38550368-C-Achr3-38550368-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001099404.2(SCN5A):c.6004G>T(p.Ala2002Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 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. A2002T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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 1 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=0.15094757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.6004G>T	p.Ala2002Ser	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.6001G>T	p.Ala2001Ser	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.6004G>T	p.Ala2002Ser	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.6001G>T	p.Ala2001Ser	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386136 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 679300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.33e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000836 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
CardioboostArm	Benign	0.0000099
CardioboostCm	Benign	0.0037
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	9.5
Dann	Uncertain	0.99
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.29	N
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.79	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.025	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T
Polyphen		0.58	P;P;.;P;.;P;P;.;.
Vest4		0.12
MutPred		0.17		.;.;Gain of phosphorylation at A2002 (P = 0.0066);.;.;Gain of phosphorylation at A2002 (P = 0.0066);.;.;.;
MVP		0.63
MPC		0.57
ClinPred		0.21	T
GERP RS		4.6
Varity_R		0.055
gMVP		0.37

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: rs771018427; hg19: chr3-38591859;