2-165139597-T-A

Position:

• chr2-165139597-T-A

Variant summary

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

The NM_006922.4(SCN3A):​c.2031A>T​(p.Thr677Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,613,204 control chromosomes in the GnomAD database, including 173,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21573 hom., cov: 31)
  • Exomes 𝑓: 0.45 (151513 hom.)
• Consequence: SCN3A NM_006922.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0720

Genes affected

SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000236283 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-165139597-T-A is Benign according to our data. Variant chr2-165139597-T-A is described in ClinVar as [Benign]. Clinvar id is 586501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.072 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN3A	NM_006922.4	c.2031A>T	p.Thr677Thr	synonymous_variant	14/28	ENST00000283254.12	NP_008853.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12	c.2031A>T	p.Thr677Thr	synonymous_variant	14/28	1	NM_006922.4	ENSP00000283254.7

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78818 AN: 151780 Hom.: 21544 Cov.: 31

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.790

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.512

GnomAD3 exomes AF: 0.511 AC: 128191 AN: 250954 Hom.: 34778 AF XY: 0.502 AC XY: 68116 AN XY: 135630

Gnomad AFR exome AF: 0.666

Gnomad AMR exome AF: 0.624

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.804

Gnomad SAS exome AF: 0.571

Gnomad FIN exome AF: 0.408

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.448 AC: 653980 AN: 1461306 Hom.: 151513 Cov.: 46 AF XY: 0.450 AC XY: 326814 AN XY: 726970

Gnomad4 AFR exome AF: 0.663

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.729

Gnomad4 SAS exome AF: 0.567

Gnomad4 FIN exome AF: 0.410

Gnomad4 NFE exome AF: 0.414

Gnomad4 OTH exome AF: 0.479

GnomAD4 genome AF: 0.519 AC: 78887 AN: 151898 Hom.: 21573 Cov.: 31 AF XY: 0.523 AC XY: 38796 AN XY: 74230

Gnomad4 AFR AF: 0.662

Gnomad4 AMR AF: 0.562

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.791

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.416

Gnomad4 OTH AF: 0.518

Alfa AF: 0.447 Hom.: 5057

Bravo AF: 0.540

Asia WGS AF: 0.696 AC: 2419 AN: 3478

EpiCase AF: 0.422

EpiControl AF: 0.420

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 76% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 71. Only high quality variants are reported. -

Epilepsy, familial focal, with variable foci 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Developmental and epileptic encephalopathy, 62 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1946892; hg19: chr2-165996107;