rs756119996

Positions:

• chr2-165323385-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001040142.2(SCN2A):​c.1901T>C​(p.Val634Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V634E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.29

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 Likely_benign. Variant got -5 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.114577085).
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.1901T>C	p.Val634Ala	missense_variant	12/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.1901T>C	p.Val634Ala	missense_variant	12/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.1901T>C	p.Val634Ala	missense_variant	12/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.1901T>C	p.Val634Ala	missense_variant	12/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250746 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000207

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 207066). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. This variant is present in population databases (rs756119996, gnomAD 0.002%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 634 of the SCN2A protein (p.Val634Ala). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2014

p.Val634Ala (V634A) GTG>GCG: c.1901 T>C in exon 12 of the SCN2A gene (NM_021007.2). The V634A variant in the SCN2A gene 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. Missense mutations in this region of the protein (R575V and D649N) have been reported in an external mutation database in association with infantile seizures and Dravet syndrome, supporting the functional importance of this region of the protein. However, the V634A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution alters a position occurs in the loop between the first and second homologous domains at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Uncertain	0.47	T;.;T;.;T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	T;.;T;.;.;.;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.90	L;L;.;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N;.;.;.;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.19	T;.;.;.;.;T;T
Sift4G	Benign	0.57	T;.;.;T;.;T;T
Polyphen		0.030	B;B;.;B;B;B;B
Vest4		0.22
MutPred		0.27		Loss of stability (P = 0.0787);Loss of stability (P = 0.0787);.;Loss of stability (P = 0.0787);Loss of stability (P = 0.0787);Loss of stability (P = 0.0787);Loss of stability (P = 0.0787);
MVP		0.42
ClinPred		0.049	T
GERP RS		3.2
Varity_R		0.053
gMVP		0.42

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: rs756119996; hg19: chr2-166179895; COSMIC: COSV99334221;