2-165377645-C-T

Position:

• chr2-165377645-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.4303C>T​(p.Arg1435Ter) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN2A NM_001040142.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.733

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 2-165377645-C-T is Pathogenic according to our data. Variant chr2-165377645-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165377645-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.4303C>T	p.Arg1435Ter	stop_gained	23/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.4303C>T	p.Arg1435Ter	stop_gained	23/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.4303C>T	p.Arg1435Ter	stop_gained	23/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.4303C>T	p.Arg1435Ter	stop_gained	23/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452298 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 722338

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 28379373, 30564305, 31780880, 32090326, 28191889, 33004838, 30813884, 26993267, Gowda2021[Case Report], 31440721, 35431799) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Developmental and epileptic encephalopathy, 11 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Sep 13, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2024

The c.4303C>T (p.R1435*) alteration, located in exon 23 (coding exon 22) of the SCN2A gene, consists of a C to T substitution at nucleotide position 4303. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1435. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. _x000D_ _x000D_ for autosomal dominant SCN2A-related neurodevelopmental disorder; however, its clinical significance for autosomal dominant SCN2A-related developmental and epileptic encephalopathy and autosomal dominant SCN2A-related benign familial infantile seizures is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with features consistent with SCN2A-related neurodevelopmental disorder, including multiple cases of reported de novo occurrence (Trump, 2016; Wolff, 2017; Fernández-Marmiesse, 2019; Zeng, 2022; Gowda, 2023). Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Neurology Department, Shenzhen Children's Hospital

Feb 16, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

This sequence change creates a premature translational stop signal (p.Arg1435*) 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: 419721). This premature translational stop signal has been observed in individual(s) with autism spectrum disorders, severe intellectual disability, and/or seizures (PMID: 26993267, 28379373). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	38
DANN	Benign	0.97
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.30	N
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.99
GERP RS		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs796053138; hg19: chr2-166234155;