3-38630277-G-T

Variant names:

• chr3-38630277-G-T
• rs41312963
• NM_001099404.2:c.392+34C>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001407186.1(SCN5A):​c.426C>A​(p.Pro142Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,426,582 control chromosomes in the GnomAD database, including 1,136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (188 hom., cov: 33)
  • Exomes 𝑓: 0.036 (948 hom.)
• Consequence: SCN5A NM_001407186.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.484

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-38630277-G-T is Benign according to our data. Variant chr3-38630277-G-T is described in ClinVar as [Benign]. Clinvar id is 257440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38630277-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.484 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.392+34C>A		intron_variant	Intron 3 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.392+34C>A		intron_variant	Intron 3 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.392+34C>A		intron_variant	Intron 3 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.392+34C>A		intron_variant	Intron 3 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6950 AN: 152182 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0468

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0341 AC: 8484 AN: 248620 Hom.: 209 AF XY: 0.0350 AC XY: 4729 AN XY: 134956

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.0171

Gnomad ASJ exome AF: 0.0481

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0501

Gnomad FIN exome AF: 0.0247

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0356 AC: 45310 AN: 1274282 Hom.: 948 Cov.: 19 AF XY: 0.0362 AC XY: 23324 AN XY: 643748

Gnomad4 AFR exome AF: 0.0826

Gnomad4 AMR exome AF: 0.0189

Gnomad4 ASJ exome AF: 0.0500

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.0501

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0348

Gnomad4 OTH exome AF: 0.0409

GnomAD4 genome AF: 0.0457 AC: 6955 AN: 152300 Hom.: 188 Cov.: 33 AF XY: 0.0444 AC XY: 3306 AN XY: 74476

Gnomad4 AFR AF: 0.0804

Gnomad4 AMR AF: 0.0280

Gnomad4 ASJ AF: 0.0527

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0469

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0434 Hom.: 47

Bravo AF: 0.0476

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.7
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41312963; hg19: chr3-38671768;