chr2-165344715-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2BA1

This summary comes from the ClinGen Evidence Repository: The c.2723A>G variant in SCN2A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 908 (p.Lys908Arg). This variant is present in gnomAD v2.1 at an allele frequency of 0.4% (1190/282874 alleles), with the highest sub-population minor allele frequency of 0.6% in the European (non-Finnish) population, which exceeds the ClinGen Epilepsy Sodium Channel threshold (0.01%) for BA1. Additionally, gnomAD v2.1.1 reports 7 individuals with this variant in a homozygous state (BS1). In summary, this variant meets the criteria to be classified as Benign for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BS1 (VCEP specifications version 1.0; 6/13/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA155058/MONDO:0100038/068

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0056 ( 37 hom. )

Consequence

SCN2A
NM_001040142.2 missense

Scores

2
9
8

Clinical Significance

Benign reviewed by expert panel B:15

Conservation

PhyloP100: 4.07
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BS2
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN2ANM_001040142.2 linkc.2723A>G p.Lys908Arg missense_variant Exon 16 of 27 ENST00000375437.7 NP_001035232.1 Q99250-1
SCN2ANM_001371246.1 linkc.2723A>G p.Lys908Arg missense_variant Exon 16 of 27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkc.2723A>G p.Lys908Arg missense_variant Exon 16 of 27 5 NM_001040142.2 ENSP00000364586.2 Q99250-1
SCN2AENST00000631182.3 linkc.2723A>G p.Lys908Arg missense_variant Exon 16 of 27 5 NM_001371246.1 ENSP00000486885.1 Q99250-2
SCN2AENST00000283256.10 linkc.2723A>G p.Lys908Arg missense_variant Exon 16 of 27 1 ENSP00000283256.6 Q99250-1

Frequencies

GnomAD3 genomes
AF:
0.00368
AC:
560
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00130
Gnomad AMI
AF:
0.00658
Gnomad AMR
AF:
0.00432
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00373
Gnomad FIN
AF:
0.000848
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00578
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00437
AC:
1098
AN:
251494
Hom.:
7
AF XY:
0.00470
AC XY:
639
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.000861
Gnomad AMR exome
AF:
0.00306
Gnomad ASJ exome
AF:
0.00188
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00447
Gnomad FIN exome
AF:
0.000970
Gnomad NFE exome
AF:
0.00674
Gnomad OTH exome
AF:
0.00554
GnomAD4 exome
AF:
0.00558
AC:
8155
AN:
1461888
Hom.:
37
Cov.:
31
AF XY:
0.00555
AC XY:
4039
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.000836
Gnomad4 AMR exome
AF:
0.00326
Gnomad4 ASJ exome
AF:
0.00161
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00472
Gnomad4 FIN exome
AF:
0.00107
Gnomad4 NFE exome
AF:
0.00643
Gnomad4 OTH exome
AF:
0.00510
GnomAD4 genome
AF:
0.00368
AC:
561
AN:
152248
Hom.:
0
Cov.:
32
AF XY:
0.00334
AC XY:
249
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00130
Gnomad4 AMR
AF:
0.00432
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00373
Gnomad4 FIN
AF:
0.000848
Gnomad4 NFE
AF:
0.00578
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00525
Hom.:
6
Bravo
AF:
0.00432
TwinsUK
AF:
0.00431
AC:
16
ALSPAC
AF:
0.00649
AC:
25
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00640
AC:
55
ExAC
AF:
0.00491
AC:
596
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00523
EpiControl
AF:
0.00634

ClinVar

Significance: Benign
Submissions summary: Benign:15
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:6
Nov 16, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 27, 2014
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 20, 2013
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. -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:3
Jun 15, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SCN2A: PM5, PP2, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Seizures, benign familial infantile, 3 Benign:2
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. -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Jun 12, 2018
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
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11;C5394520:Episodic ataxia, type 9 Benign:1
Dec 02, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Complex neurodevelopmental disorder Benign:1
May 09, 2024
ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The c.2723A>G variant in SCN2A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 908 (p.Lys908Arg). This variant is present in gnomAD v2.1 at an allele frequency of 0.4% (1190/282874 alleles), with the highest sub-population minor allele frequency of 0.6% in the European (non-Finnish) population, which exceeds the ClinGen Epilepsy Sodium Channel threshold (0.01%) for BA1. Additionally, gnomAD v2.1.1 reports 7 individuals with this variant in a homozygous state (BS1). In summary, this variant meets the criteria to be classified as Benign for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BS1 (VCEP specifications version 1.0; 6/13/2023) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;.;T;.;D;D;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.75
T;.;T;.;.;.;T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.010
T;T;T;T;T;T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.3
L;L;.;L;L;L;L
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-2.2
N;.;.;.;.;N;N
REVEL
Uncertain
0.43
Sift
Uncertain
0.015
D;.;.;.;.;D;D
Sift4G
Benign
0.24
T;.;.;T;.;T;T
Polyphen
1.0
D;B;.;B;D;D;B
Vest4
0.24
MVP
0.97
ClinPred
0.024
T
GERP RS
5.7
Varity_R
0.63
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2228980; hg19: chr2-166201225; API