rs2121371

Positions:

• chr2-165313617-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040142.2(SCN2A):​c.1035-3T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001398
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.188

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 -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/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.1035-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000375437.7
SCN2A	NM_001371246.1	c.1035-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.1035-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.1035-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.816 AC: 123877 AN: 151870 Hom.: 50691 Cov.: 31

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

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.: 50 AF XY: 0.820 AC XY: 595988 AN XY: 726718

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.: 31 AF XY: 0.811 AC XY: 60257 AN XY: 74270

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:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Seizures, benign familial infantile, 3 Benign:2

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. -
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	-0.50
CADD	Benign	12
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

Other links and lift over

dbSNP: rs2121371; hg19: chr2-166170127;