chr2-165388685-G-A

Position:

• chr2-165388685-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.4879G>A​(p.Val1627Met) variant causes a missense 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 9.98

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 15 ACMG points.

• PM1: In a repeat IV (size 298) in uniprot entity SCN2A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN2A. . Trascript score misZ 8.7114 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 2-165388685-G-A is Pathogenic according to our data. Variant chr2-165388685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 207018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.4879G>A	p.Val1627Met	missense_variant	27/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.4879G>A	p.Val1627Met	missense_variant	27/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.4879G>A	p.Val1627Met	missense_variant	27/27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.4879G>A	p.Val1627Met	missense_variant	27/27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.4879G>A	p.Val1627Met	missense_variant	27/27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Oct 25, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 207018). This missense change has been observed in individual(s) with epilepsy and SCN2A-related disorders (PMID: 28379373; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1627 of the SCN2A protein (p.Val1627Met). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2018

- -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

GeneDx

Oct 24, 2013

p.Val1627Met (GTG>ATG): c.4879 G>A in exon 27 of the SCN2A gene (NM_021007.2). The Val627Met missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution, as Valine and Methionine are both uncharged, non-polar amino acids. It alters a highly conserved position in the S4 segment of the fourth transmembrane domain of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether Val627Met is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;T;.;D;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;.;M;M;M;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.6	D;.;.;.;.;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Uncertain	0.0070	D;.;.;D;.;D;D
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.70
MutPred		0.70		Gain of MoRF binding (P = 0.1438);Gain of MoRF binding (P = 0.1438);.;Gain of MoRF binding (P = 0.1438);Gain of MoRF binding (P = 0.1438);Gain of MoRF binding (P = 0.1438);Gain of MoRF binding (P = 0.1438);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs796053156; hg19: chr2-166245195;