2-165323269-T-C

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.1785T>C(p.Asp595=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,178 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (7 hom., cov: 32)
  • Exomes 𝑓: 0.013 (146 hom.)
• Consequence: SCN2A NM_001040142.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.633

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=-0.53).
• BP6: Variant 2-165323269-T-C is Benign according to our data. Variant chr2-165323269-T-C is described in ClinVar as [Benign]. Clinvar id is 130217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165323269-T-C is described in Lovd as [Likely_benign]. Variant chr2-165323269-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.633 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00999 (1522/152284) while in subpopulation AMR AF= 0.0176 (270/15300). AF 95% confidence interval is 0.0159. There are 7 homozygotes in gnomad4. There are 733 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.1785T>C	p.Asp595=	synonymous_variant	12/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.1785T>C	p.Asp595=	synonymous_variant	12/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.1785T>C	p.Asp595=	synonymous_variant	12/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.1785T>C	p.Asp595=	synonymous_variant	12/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1524 AN: 152166 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00952 AC: 2392 AN: 251292 Hom.: 18 AF XY: 0.00970 AC XY: 1317 AN XY: 135814

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00490

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0130 AC: 19046 AN: 1461894 Hom.: 146 Cov.: 32 AF XY: 0.0126 AC XY: 9189 AN XY: 727248

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.00819

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.00569

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.00999 AC: 1522 AN: 152284 Hom.: 7 Cov.: 32 AF XY: 0.00984 AC XY: 733 AN XY: 74456

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.0176

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0113 Hom.: 6

Bravo AF: 0.0106

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0155

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 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	Genetic Services Laboratory, University of Chicago	Mar 28, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN2A: BP4, BP7, BS1, BS2 -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2017

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

- -

Seizures, benign familial infantile, 3 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	2.5
Dann	Benign	0.52

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: rs141815642; hg19: chr2-166179779;