2-165297053-C-T

Variant names:

• chr2-165297053-C-T
• rs387906683
• NM_001040142.2:c.304C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.304C>T​(p.Arg102*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165297053-C-T is Pathogenic according to our data. Variant chr2-165297053-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165297053-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.304C>T	p.Arg102*	stop_gained	Exon 3 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.304C>T	p.Arg102*	stop_gained	Exon 3 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.304C>T	p.Arg102*	stop_gained	Exon 3 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.304C>T	p.Arg102*	stop_gained	Exon 3 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.304C>T	p.Arg102*	stop_gained	Exon 3 of 27	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.304C>T	p.Arg102*	stop_gained	Exon 3 of 11	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:3

Nov 02, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 13, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Sep 28, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published patch clamp studies demonstrate the variant results in absent channel current, demonstrating loss of function (Kamiya et al., 2004); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27535533, 31785789, 33004838, 15028761, 28135719, 28191890, 19786696, 30175250, 31558572, 29635106, 32090326, 30813884, 33841294, 33851778, 34894057, 28600779) -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1

Aug 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with SCN2A-related conditions (PMID: 15028761, 33851778, 34894057). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg102*) in the SCN2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN2A are known to be pathogenic (PMID: 28379373). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29885). -

Episodic ataxia, type 9 Pathogenic:1

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Complex neurodevelopmental disorder Pathogenic:1

Apr 20, 2018

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-20 and interpreted as Pathogenic. Variant was initially reported on 2017-05-23 by GTR ID of laboratory name Klinikum rechts der Isar Technische Universitat Munchen . The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.94, 0.94, 0.94
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs387906683; hg19: chr2-166153563;