rs121917751

chr2-165344666-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001040142.2(SCN2A):c.2674G>A(p.Val892Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V892F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.87

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 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-165344666-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2947342.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SCN2A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 2-165344666-G-A is Pathogenic according to our data. Variant chr2-165344666-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.2674G>A	p.Val892Ile	missense_variant	16/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.2674G>A	p.Val892Ile	missense_variant	16/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.2674G>A	p.Val892Ile	missense_variant	16/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.2674G>A	p.Val892Ile	missense_variant	16/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 15, 2018	SCN2A NM_021007.2 exon 16 p.Val892Ile (c.2674G>A): This variant has been reported in the literature in at least 2 individuals with Benign Familial Neonatal-Infantile Epilepsy (BFNIE), segregating with disease in at least 5 affected family members (Berkovic 2004 PMID:15048894, Zeng 2018 PMID:29215089). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:12878). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 892 of the SCN2A protein (p.Val892Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with benign familial neonatal-infantile seizures (PMID: 15048894, 29215089). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12878). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2021	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This substitution is predicted to be within the transmembrane segment S5 of the second homologous domain; This variant is associated with the following publications: (PMID: 15048894, 28717674, 29215089, 29655203, 29429461, 32090326) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Seizures, benign familial infantile, 3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
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;C5394520:Episodic ataxia, type 9 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 11, 2021

SCN2A NM_021007.2 exon 16 p.Val892Ile (c.2674G>A): This variant has been reported in the literature in at least 2 individuals with Benign Familial Neonatal-Infantile Epilepsy (BFNIE), segregating with disease in at least 5 affected family members (Berkovic 2004 PMID:15048894, Zeng 2018 PMID:29215089). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:12878). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;T;.;D;D;.
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.41	N;N;.;N;N;N;N
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.97	N;.;.;.;.;N;N
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Benign	0.62	T;.;.;T;.;T;T
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.73
MutPred		0.88		Loss of catalytic residue at V892 (P = 0.0125);Loss of catalytic residue at V892 (P = 0.0125);.;Loss of catalytic residue at V892 (P = 0.0125);Loss of catalytic residue at V892 (P = 0.0125);Loss of catalytic residue at V892 (P = 0.0125);Loss of catalytic residue at V892 (P = 0.0125);
MVP		0.99
ClinPred		0.80	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs121917751; hg19: chr2-166201176;