rs2121371

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040142.2(SCN2A):c.1035-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 1,612,776 control chromosomes in the GnomAD database, including 548,643 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 50729 hom., cov: 31)

Exomes 𝑓: 0.82 ( 497914 hom. )

Consequence

SCN2A
NM_001040142.2 splice_region, intron

Scores

Splicing: ADA: 0.0001398

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.188

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]

SCN2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-165313617-T-C is Benign according to our data. Variant chr2-165313617-T-C is described in ClinVar as [Benign]. Clinvar id is 130216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165313617-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2 link	c.1035-3T>C		splice_region_variant, intron_variant	Intron 8 of 26	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.1035-3T>C		splice_region_variant, intron_variant	Intron 8 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2A	ENST00000375437.7 link	c.1035-3T>C	splice_region_variant, intron_variant	Intron 8 of 26	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.1035-3T>C	splice_region_variant, intron_variant	Intron 8 of 26	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000283256.10 link	c.1035-3T>C	splice_region_variant, intron_variant	Intron 8 of 26	1		ENSP00000283256.6	Q99250-1
SCN2A	ENST00000424833.5 link	c.1035-3T>C	splice_region_variant, intron_variant	Intron 8 of 10	1		ENSP00000406454.2	F6U291

Frequencies

GnomAD3 genomes

AF:

0.816

AC:

123877

AN:

151870

Hom.:

50691

Cov.:

show subpopulations

Gnomad AFR

AF:

0.808

Gnomad AMI

AF:

0.749

Gnomad AMR

AF:

0.824

Gnomad ASJ

AF:

0.781

Gnomad EAS

AF:

0.749

Gnomad SAS

AF:

0.732

Gnomad FIN

AF:

0.769

Gnomad MID

AF:

0.741

Gnomad NFE

AF:

0.840

Gnomad OTH

AF:

0.811

GnomAD3 exomes

AF:

0.802

AC:

201564

AN:

251294

Hom.:

81134

AF XY:

0.797

AC XY:

108218

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.809

Gnomad AMR exome

AF:

0.816

Gnomad ASJ exome

AF:

0.780

Gnomad EAS exome

AF:

0.780

Gnomad SAS exome

AF:

0.709

Gnomad FIN exome

AF:

0.767

Gnomad NFE exome

AF:

0.835

Gnomad OTH exome

AF:

0.778

GnomAD4 exome

AF:

0.824

AC:

1203871

AN:

1460788

Hom.:

497914

Cov.:

AF XY:

0.820

AC XY:

595988

AN XY:

726718

show subpopulations

Gnomad4 AFR exome

AF:

0.799

Gnomad4 AMR exome

AF:

0.811

Gnomad4 ASJ exome

AF:

0.784

Gnomad4 EAS exome

AF:

0.684

Gnomad4 SAS exome

AF:

0.714

Gnomad4 FIN exome

AF:

0.764

Gnomad4 NFE exome

AF:

0.844

Gnomad4 OTH exome

AF:

0.808

GnomAD4 genome

AF:

0.816

AC:

123967

AN:

151988

Hom.:

50729

Cov.:

AF XY:

0.811

AC XY:

60257

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.808

Gnomad4 AMR

AF:

0.824

Gnomad4 ASJ

AF:

0.781

Gnomad4 EAS

AF:

0.749

Gnomad4 SAS

AF:

0.731

Gnomad4 FIN

AF:

0.769

Gnomad4 NFE

AF:

0.840

Gnomad4 OTH

AF:

0.812

Alfa

AF:

0.827

Hom.:

25678

Bravo

AF:

0.820

Asia WGS

AF:

0.739

AC:

2568

AN:

3478

EpiCase

AF:

0.828

EpiControl

AF:

0.834

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

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

- -

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

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 89. Only high quality variants are reported. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 11

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 31, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia, type 9

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.010

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over