chr3-38622460-A-T

Position:

chr3-38622460-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The ENST00000423572.7(SCN5A):c.422T>A(p.Ile141Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I141F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

SCN5A
ENST00000423572.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.32

Variant links:

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]

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38622461-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2734486.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.422T>A	p.Ile141Asn	missense_variant	4/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.422T>A	p.Ile141Asn	missense_variant	4/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.422T>A	p.Ile141Asn	missense_variant	4/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.422T>A	p.Ile141Asn	missense_variant	4/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245302

Hom.:

AF XY:

0.00000752

AC XY:

AN XY:

132952

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

May 02, 2018

- -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 141 of the SCN5A protein (p.Ile141Asn). This variant is present in population databases (rs772186966, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 463335). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant disrupts the p.Ile141 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25210054). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Benign

0.083

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

.;.;.;.;.;D;.;.;.;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D;D;.;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

.;M;.;.;.;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.2

D;D;D;D;D;D;D;D;D;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;.;D;D;.;.;.

Vest4

0.95

MutPred

0.64

Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);Loss of stability (P = 0.0821);

MVP

0.96

MPC

1.5

ClinPred

0.99

GERP RS

4.0

Varity_R

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over