rs1946892

Variant names:

• chr2-165139597-T-A
• rs1946892
• NM_006922.4:c.2031A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-165139597-T-A
• chr2-165139597-T-C
• chr2-165139597-T-G

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. T677T) has been classified as Likely 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
• Publications: 19 publications found

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]

SCN3A Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 62

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy, familial focal, with variable foci 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236283 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006922.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3A	NM_006922.4	MANE Select	c.2031A>T	p.Thr677Thr	synonymous	Exon 14 of 28	NP_008853.3
	SCN3A	NM_001081676.2		c.1884A>T	p.Thr628Thr	synonymous	Exon 14 of 28	NP_001075145.1	Q9NY46-4
	SCN3A	NM_001081677.2		c.1884A>T	p.Thr628Thr	synonymous	Exon 14 of 28	NP_001075146.1	Q9NY46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3A	ENST00000283254.12	TSL:1 MANE Select	c.2031A>T	p.Thr677Thr	synonymous	Exon 14 of 28	ENSP00000283254.7	Q9NY46-3
	SCN3A	ENST00000409101.7	TSL:1	c.1884A>T	p.Thr628Thr	synonymous	Exon 14 of 28	ENSP00000386726.3	Q9NY46-2
	SCN3A	ENST00000706067.1		c.1980A>T	p.Thr660Thr	synonymous	Exon 14 of 28	ENSP00000516211.1	A0A994J5P2

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

GnomAD2 exomes AF: 0.511 AC: 128191 AN: 250954 AF XY: 0.502

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 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

African (AFR) AF: 0.663 AC: 22180 AN: 33446

American (AMR) AF: 0.615 AC: 27471 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 13023 AN: 26124

East Asian (EAS) AF: 0.729 AC: 28928 AN: 39682

South Asian (SAS) AF: 0.567 AC: 48883 AN: 86250

European-Finnish (FIN) AF: 0.410 AC: 21871 AN: 53370

Middle Eastern (MID) AF: 0.510 AC: 2938 AN: 5764

European-Non Finnish (NFE) AF: 0.414 AC: 459748 AN: 1111608

Other (OTH) AF: 0.479 AC: 28938 AN: 60364

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

African (AFR) AF: 0.662 AC: 27440 AN: 41426

American (AMR) AF: 0.562 AC: 8564 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1745 AN: 3468

East Asian (EAS) AF: 0.791 AC: 4053 AN: 5126

South Asian (SAS) AF: 0.587 AC: 2821 AN: 4808

European-Finnish (FIN) AF: 0.409 AC: 4313 AN: 10548

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28304 AN: 67966

Other (OTH) AF: 0.518 AC: 1093 AN: 2110

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Developmental and epileptic encephalopathy, 62 (1)
-	-	1	Epilepsy, familial focal, with variable foci 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.77
PhyloP100		-0.072
Mutation Taster		=79/21	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1946892; hg19: chr2-165996107; COSMIC: COSV108047251;