rs2060198

Positions:

• chr2-165388720-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_001040142.2(SCN2A):​c.4914T>A​(p.Arg1638=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,746 control chromosomes in the GnomAD database, including 66,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5375 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61498 hom.)
• Consequence: SCN2A NM_001040142.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.217

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=-0.54).
• BP6: Variant 2-165388720-T-A is Benign according to our data. Variant chr2-165388720-T-A is described in ClinVar as [Benign]. Clinvar id is 130223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165388720-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.217 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.4914T>A	p.Arg1638=	synonymous_variant	27/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.4914T>A	p.Arg1638=	synonymous_variant	27/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.4914T>A	p.Arg1638=	synonymous_variant	27/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.4914T>A	p.Arg1638=	synonymous_variant	27/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38787 AN: 151906 Hom.: 5374 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.255

GnomAD3 exomes AF: 0.283 AC: 71245 AN: 251338 Hom.: 10588 AF XY: 0.291 AC XY: 39474 AN XY: 135830

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.215

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.287 AC: 418992 AN: 1461722 Hom.: 61498 Cov.: 38 AF XY: 0.289 AC XY: 210420 AN XY: 727160

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.408

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.284

GnomAD4 genome AF: 0.255 AC: 38791 AN: 152024 Hom.: 5375 Cov.: 32 AF XY: 0.261 AC XY: 19379 AN XY: 74300

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.247

Gnomad4 SAS AF: 0.318

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.283

Gnomad4 OTH AF: 0.253

Alfa AF: 0.282 Hom.: 2034

Bravo AF: 0.236

Asia WGS AF: 0.270 AC: 939 AN: 3478

EpiCase AF: 0.283

EpiControl AF: 0.278

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
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 47% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 44. Only high quality variants are reported. -

Seizures, benign familial infantile, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Developmental and epileptic encephalopathy, 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2015

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Episodic ataxia, type 9 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	-0.54
CADD	Benign	9.0
DANN	Benign	0.65

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: rs2060198; hg19: chr2-166245230; COSMIC: COSV51843027;