rs918734456

Variant names:

• chr2-165374830-A-G
• rs918734456
• NM_001040142.2:c.4118A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-165374830-A-G
• chr2-165374830-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001040142.2(SCN2A):​c.4118A>G​(p.Glu1373Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.29
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 11 uncertain in NM_001040142.2
• 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 genetic developmental and epileptic encephalopathy, episodic ataxia, type 9, seizures, benign familial infantile, 3, complex neurodevelopmental disorder, benign familial neonatal-infantile seizures, Dravet syndrome, infantile spasms, developmental and epileptic encephalopathy, 11, intellectual disability, benign familial infantile epilepsy, malignant migrating partial seizures of infancy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.4118A>G	p.Glu1373Gly	missense_variant	Exon 22 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.4118A>G	p.Glu1373Gly	missense_variant	Exon 22 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.4118A>G	p.Glu1373Gly	missense_variant	Exon 22 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.4118A>G	p.Glu1373Gly	missense_variant	Exon 22 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.4118A>G	p.Glu1373Gly	missense_variant	Exon 22 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461454 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000224 AC: 1 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111728

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1373 of the SCN2A protein (p.Glu1373Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 574739). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Oct 03, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the third homologous domain -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;T;.;D;D;.
Eigen	Benign	-0.044
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.63	T;.;T;.;.;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.4	M;M;.;M;M;M;M
PhyloP100		3.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N;.;.;.;.;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.23	T;.;.;.;.;T;T
Sift4G	Uncertain	0.048	D;.;.;D;.;D;D
Polyphen		0.079	B;B;.;B;B;B;B
Vest4		0.37
MutPred		0.45		Gain of catalytic residue at G1372 (P = 0.0732);Gain of catalytic residue at G1372 (P = 0.0732);.;Gain of catalytic residue at G1372 (P = 0.0732);Gain of catalytic residue at G1372 (P = 0.0732);Gain of catalytic residue at G1372 (P = 0.0732);Gain of catalytic residue at G1372 (P = 0.0732);
MVP		0.75
ClinPred		0.82	D
GERP RS		4.4
Varity_R		0.30
gMVP		0.93
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs918734456; hg19: chr2-166231340;