3-38581092-G-T

Variant summary

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

The NM_001099404.2(SCN5A):c.3067C>A(p.Arg1023Ser) 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. 14/23 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. R1023H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.53

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 chr3-38581091-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, SCN5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.2113088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3067C>A	p.Arg1023Ser	missense_variant	17/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3067C>A	p.Arg1023Ser	missense_variant	17/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3067C>A	p.Arg1023Ser	missense_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3067C>A	p.Arg1023Ser	missense_variant	17/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostArm	Benign	0.0000026
CardioboostCm	Benign	0.0031
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.70	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	0.87	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.30	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.87	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.74	T;T;T;T;T;T;T;T;T
Polyphen		0.0030	B;B;.;B;.;B;P;.;.
Vest4		0.19
MutPred		0.50		Gain of phosphorylation at R1023 (P = 0.023);Gain of phosphorylation at R1023 (P = 0.023);Gain of phosphorylation at R1023 (P = 0.023);Gain of phosphorylation at R1023 (P = 0.023);Gain of phosphorylation at R1023 (P = 0.023);Gain of phosphorylation at R1023 (P = 0.023);Gain of phosphorylation at R1023 (P = 0.023);Gain of phosphorylation at R1023 (P = 0.023);Gain of phosphorylation at R1023 (P = 0.023);
MVP		0.72
MPC		0.15
ClinPred		0.72	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.63

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: rs745435760; hg19: chr3-38622583;