2-165297053-C-T

Position:

• chr2-165297053-C-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]

SCN2A (HGNC:):

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/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.304C>T	p.Arg102*	stop_gained	3/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.304C>T	p.Arg102*	stop_gained	3/27	ENST00000631182.3	NP_001358175.1

Ensembl

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 13, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 17, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Nov 02, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2022	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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29885). 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). -

Episodic ataxia, type 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 17, 2024

- -

Complex neurodevelopmental disorder Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Apr 20, 2018

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;