rs1135401948

chr3-38597778-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001099404.2(SCN5A):c.2213A>C(p.His738Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H738H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a repeat II (size 270) in uniprot entity SCN5A_HUMAN there are 72 pathogenic changes around while only 4 benign (95%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.2213A>C	p.His738Pro	missense_variant	14/28	ENST00000413689.6
SCN5A	NM_000335.5	c.2213A>C	p.His738Pro	missense_variant	14/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2213A>C	p.His738Pro	missense_variant	14/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2213A>C	p.His738Pro	missense_variant	14/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Mar 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-9.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;P;P;.;.
Vest4		0.94
MutPred		0.69		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.99

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: rs1135401948; hg19: chr3-38639269;