chr3-38550459-A-G

Variant names:

• chr3-38550459-A-G
• rs972777761
• NM_001099404.2:c.5913T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001099404.2(SCN5A):​c.5913T>C​(p.Thr1971Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1971T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN5A NM_001099404.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.76
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-38550459-A-G is Benign according to our data. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550459-A-G is described in CliVar as Likely_benign. Clinvar id is 413941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.76 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5913T>C	p.Thr1971Thr	synonymous_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5910T>C	p.Thr1970Thr	synonymous_variant	Exon 28 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5913T>C	p.Thr1971Thr	synonymous_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5910T>C	p.Thr1970Thr	synonymous_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 243346 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452954 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721260

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 84602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106668

Other (OTH) AF: 0.00 AC: 0 AN: 59960

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

May 17, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 23, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.41
DANN	Benign	0.58
PhyloP100		-4.8

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

Other links and lift over

dbSNP: rs972777761; hg19: chr3-38591950;