rs1060503102

Variant names:

• chr2-165388682-C-T
• rs1060503102
• NM_001040142.2:c.4876C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.4876C>T​(p.Arg1626*) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.06

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165388682-C-T is Pathogenic according to our data. Variant chr2-165388682-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165388682-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.4876C>T	p.Arg1626*	stop_gained	Exon 27 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.4876C>T	p.Arg1626*	stop_gained	Exon 27 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.4876C>T	p.Arg1626*	stop_gained	Exon 27 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.4876C>T	p.Arg1626*	stop_gained	Exon 27 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.4876C>T	p.Arg1626*	stop_gained	Exon 27 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jun 24, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4876C>T (p.R1626*) alteration, located in exon 27 (coding exon 26) of the SCN2A gene, consists of a C to T substitution at nucleotide position 4876. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1626. This alteration occurs at the 3' terminus of the SCN2A gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 19% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD), the SCN2A c.4876C>T alteration was not observed, with coverage at this position. This variant was reported to occur de novo in an autism cohort (Stessman, 2017). Based on the available evidence, this alteration is classified as likely pathogenic. -

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

Sep 22, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Family studies have indicated that this variant was not present in the parents of an individual with clinical features of epilepsy, which suggests that it was de novo in that affected individual (Invitae). A missense change at the same codon (p.Arg1626Gln) has been reported as a de novo variant in 2 individuals affected with seizures (PMID: 25937001, 25473036). This suggests that this amino acid residue is essential for proper function of the SCN2A protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN2A-related disease. This sequence change results in a premature translational stop signal in the last exon of the SCN2A mRNA at codon 1626 (p.Arg1626*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated SCN2A protein. -

not provided Pathogenic:1

Nov 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 380 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28191889, 33004838) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.94
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060503102; hg19: chr2-166245192; COSMIC: COSV51837686;