rs796053138

Variant names:

• chr2-165377645-C-G
• rs796053138
• NM_001040142.2:c.4303C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-165377645-C-G
• chr2-165377645-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001040142.2(SCN2A):​c.4303C>G​(p.Arg1435Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 362 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Trascript score misZ: 8.7114 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.4303C>G	p.Arg1435Gly	missense_variant	Exon 23 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.4303C>G	p.Arg1435Gly	missense_variant	Exon 23 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.4303C>G	p.Arg1435Gly	missense_variant	Exon 23 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.4303C>G	p.Arg1435Gly	missense_variant	Exon 23 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.4303C>G	p.Arg1435Gly	missense_variant	Exon 23 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 28, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg1435Gly (CGA>GGA): c.4303 C>G in exon 23 of the SCN2A gene (NM_021007.2). The Arg1435Gly 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 non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged, non-polar Glycine residue. It alters a position in the loop between the S5 and S6 segments of the third transmembrane domain that is conserved across species, and 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 Arg1435Gly is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D;.;T;.;D;D;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.87	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.6	M;M;.;M;M;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.2	D;.;.;.;.;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;.;.;.;.;D;D
Sift4G	Uncertain	0.032	D;.;.;D;.;D;D
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.85
MutPred		0.55		Loss of stability (P = 0.0325);Loss of stability (P = 0.0325);.;Loss of stability (P = 0.0325);Loss of stability (P = 0.0325);Loss of stability (P = 0.0325);Loss of stability (P = 0.0325);
MVP		1.0
ClinPred		1.0	D
GERP RS		0.24
Varity_R		0.79
gMVP		0.98

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: rs796053138; hg19: chr2-166234155;