chr2-165313617-T-C

Variant names:

• chr2-165313617-T-C
• rs2121371
• NM_001040142.2:c.1035-3T>C

Variant summary

Our verdict is Benign. The variant received -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, 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
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.1035-3T>C		splice_region_variant, intron_variant	Intron 8 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.1035-3T>C		splice_region_variant, intron_variant	Intron 8 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

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

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

GnomAD2 exomes AF: 0.802 AC: 201564 AN: 251294 AF XY: 0.797

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 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

African (AFR) AF: 0.799 AC: 26708 AN: 33438

American (AMR) AF: 0.811 AC: 36269 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 20453 AN: 26094

East Asian (EAS) AF: 0.684 AC: 27162 AN: 39682

South Asian (SAS) AF: 0.714 AC: 61590 AN: 86230

European-Finnish (FIN) AF: 0.764 AC: 40831 AN: 53410

Middle Eastern (MID) AF: 0.708 AC: 4074 AN: 5758

European-Non Finnish (NFE) AF: 0.844 AC: 938010 AN: 1111136

Other (OTH) AF: 0.808 AC: 48774 AN: 60340

GnomAD4 genome AF: 0.816 AC: 123967 AN: 151988 Hom.: 50729 Cov.: 31 AF XY: 0.811 AC XY: 60257 AN XY: 74270

African (AFR) AF: 0.808 AC: 33505 AN: 41462

American (AMR) AF: 0.824 AC: 12563 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2713 AN: 3472

East Asian (EAS) AF: 0.749 AC: 3847 AN: 5136

South Asian (SAS) AF: 0.731 AC: 3516 AN: 4810

European-Finnish (FIN) AF: 0.769 AC: 8136 AN: 10576

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57083 AN: 67972

Other (OTH) AF: 0.812 AC: 1708 AN: 2104

Alfa AF: 0.824 Hom.: 34019

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

Submissions by phenotype

not specified Benign:5

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

May 06, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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. -

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	12
DANN	Benign	0.65
PhyloP100		0.19
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2121371; hg19: chr2-166170127;