rs140194137

Variant names:

• chr2-165367290-G-A
• rs140194137
• NM_001040142.2:c.3594G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001040142.2(SCN2A):​c.3594G>A​(p.Arg1198Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000758 in 1,614,102 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (5 hom.)
• Consequence: SCN2A NM_001040142.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0250

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-165367290-G-A is Benign according to our data. Variant chr2-165367290-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 139013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165367290-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00102 (155/152258) while in subpopulation SAS AF= 0.0027 (13/4820). AF 95% confidence interval is 0.00159. There are 4 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 155 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.3594G>A	p.Arg1198Arg	synonymous_variant	Exon 19 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.3594G>A	p.Arg1198Arg	synonymous_variant	Exon 19 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.3594G>A	p.Arg1198Arg	synonymous_variant	Exon 19 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.3594G>A	p.Arg1198Arg	synonymous_variant	Exon 19 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.3594G>A	p.Arg1198Arg	synonymous_variant	Exon 19 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152140 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000835 AC: 210 AN: 251384 Hom.: 2 AF XY: 0.00107 AC XY: 146 AN XY: 135858

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00372

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000731 AC: 1068 AN: 1461844 Hom.: 5 Cov.: 31 AF XY: 0.000811 AC XY: 590 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00352

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000605

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152258 Hom.: 4 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74444

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000945 Hom.: 0

Bravo AF: 0.00115

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 06, 2014

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. -

Inborn genetic diseases Benign:1

Aug 19, 2016

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. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN2A: BP4, BP7 -

Seizures, benign familial infantile, 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.6
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs140194137; hg19: chr2-166223800; COSMIC: COSV51836238;