rs17183814

chr2-165295879-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001040142.2(SCN2A):c.56G>A(p.Arg19Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,614,062 control chromosomes in the GnomAD database, including 4,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (359 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4634 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.48

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015491843).
• BP6: Variant 2-165295879-G-A is Benign according to our data. Variant chr2-165295879-G-A is described in ClinVar as [Benign]. Clinvar id is 130224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165295879-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.56G>A	p.Arg19Lys	missense_variant	2/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.56G>A	p.Arg19Lys	missense_variant	2/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.56G>A	p.Arg19Lys	missense_variant	2/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.56G>A	p.Arg19Lys	missense_variant	2/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 9706 AN: 152150 Hom.: 358 Cov.: 32

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0962

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0381

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0704

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0843 AC: 21148 AN: 250808 Hom.: 1097 AF XY: 0.0845 AC XY: 11453 AN XY: 135540

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.0620

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0424

Gnomad NFE exome AF: 0.0694

Gnomad OTH exome AF: 0.0700

GnomAD4 exome AF: 0.0764 AC: 111622 AN: 1461794 Hom.: 4634 Cov.: 32 AF XY: 0.0776 AC XY: 56442 AN XY: 727194

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.0644

Gnomad4 EAS exome AF: 0.0987

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0452

Gnomad4 NFE exome AF: 0.0741

Gnomad4 OTH exome AF: 0.0743

GnomAD4 genome AF: 0.0637 AC: 9706 AN: 152268 Hom.: 359 Cov.: 32 AF XY: 0.0645 AC XY: 4800 AN XY: 74456

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.0963

Gnomad4 ASJ AF: 0.0652

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0381

Gnomad4 NFE AF: 0.0704

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0697 Hom.: 770

Bravo AF: 0.0666

TwinsUK AF: 0.0698 AC: 259

ALSPAC AF: 0.0820 AC: 316

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.0716 AC: 616

ExAC AF: 0.0818 AC: 9935

Asia WGS AF: 0.114 AC: 397 AN: 3478

EpiCase AF: 0.0700

EpiControl AF: 0.0670

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Seizures, benign familial infantile, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	33
Dann	Benign	0.96
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T;T;.;.;.;.;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	0.85	P;P;P;P
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N;N;.;.;.;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.21	T;T;.;.;.;T;T
Sift4G	Benign	0.48	T;T;.;T;.;T;T
Polyphen		0.0010, 0.0020	.;B;B;B;B;B;B
Vest4		0.090, 0.062, 0.072, 0.088
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.38
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17183814; hg19: chr2-166152389; COSMIC: COSV51834563;