chr2-165127774-C-T

Variant names:

• chr2-165127774-C-T
• rs140990288
• NM_006922.4:c.3250G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.3250G>A variant in SCN3A is a missense variant predicted to cause the subsitution of valine by isoleucine at amino acid 1084 (p.Val1084Ile). The variant is present in 0.5% of the total population, and 0.7% of the European (non-Finnish) population, in gnomAD v2.1.1, which exceeds the threshold of 0.01% for BA1. The in silico predictor REVEL score for this variant is 0.155 which meets the criteria for BP4_Moderate. The variant has not been reported in an individual with developmental and epileptic encepathalopathy in the reported literature to date, and does not fall within a pathogenic enriched region. In summary, this variant meets the criteria to be classified as benign for autosomal dominant developmental and epileptic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BP4_Moderate (specification v1.0; approved 6/27/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214587/MONDO:0100062/069

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (68 hom.)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.0730
• Publications: 11 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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.3250G>A	p.Val1084Ile	missense	Exon 18 of 28	NP_008853.3
	SCN3A	NM_001081676.2		c.3103G>A	p.Val1035Ile	missense	Exon 18 of 28	NP_001075145.1	Q9NY46-4
	SCN3A	NM_001081677.2		c.3103G>A	p.Val1035Ile	missense	Exon 18 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.3250G>A	p.Val1084Ile	missense	Exon 18 of 28	ENSP00000283254.7	Q9NY46-3
	SCN3A	ENST00000409101.7	TSL:1	c.3103G>A	p.Val1035Ile	missense	Exon 18 of 28	ENSP00000386726.3	Q9NY46-2
	SCN3A	ENST00000706067.1		c.3199G>A	p.Val1067Ile	missense	Exon 18 of 28	ENSP00000516211.1	A0A994J5P2

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 783 AN: 152152 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00858

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00514 AC: 1293 AN: 251398 AF XY: 0.00526

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00731

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00783 AC: 11441 AN: 1461840 Hom.: 68 Cov.: 32 AF XY: 0.00766 AC XY: 5574 AN XY: 727226

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00548 AC: 245 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00540 AC: 466 AN: 86258

European-Finnish (FIN) AF: 0.00202 AC: 108 AN: 53420

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.00921 AC: 10238 AN: 1111976

Other (OTH) AF: 0.00517 AC: 312 AN: 60394

GnomAD4 genome AF: 0.00514 AC: 783 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00488 AC XY: 363 AN XY: 74444

African (AFR) AF: 0.00161 AC: 67 AN: 41548

American (AMR) AF: 0.00464 AC: 71 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00859 AC: 584 AN: 68020

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00678 Hom.: 12

Bravo AF: 0.00522

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00550 AC: 668

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00640

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Epilepsy, familial focal, with variable foci 4;C4693699:Developmental and epileptic encephalopathy, 62 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.29
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.073
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.15
Sift	Benign	0.96	T
Sift4G	Benign	0.83	T
Polyphen		0.0060	B
Vest4		0.050
MVP		0.26
MPC		0.55
ClinPred		0.0013	T
GERP RS		4.1
Varity_R		0.017
gMVP		0.33
Mutation Taster		=97/3	polymorphism

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: rs140990288; hg19: chr2-165984284; COSMIC: COSV51826961;