2-165294039-G-A

Position:

• chr2-165294039-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000283256(SCN2A):​c.-148G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0076 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN2A ENST00000283256 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.385

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1734G>A		intron_variant		ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1734G>A		intron_variant		ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000283256	c.-148G>A		5_prime_UTR_variant	1/27	1		ENSP00000283256.6
SCN2A	ENST00000375437.7	c.-51-1734G>A		intron_variant		5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1734G>A		intron_variant		5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1734G>A		intron_variant		1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1111 AN: 49938 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0248

Gnomad AMR AF: 0.0208

Gnomad ASJ AF: 0.0140

Gnomad EAS AF: 0.0270

Gnomad SAS AF: 0.0183

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.0288

Gnomad OTH AF: 0.0269

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00758 AC: 1658 AN: 218744 Hom.: 0 Cov.: 0 AF XY: 0.00726 AC XY: 747 AN XY: 102842

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.00267

Gnomad4 EAS exome AF: 0.00893

Gnomad4 SAS exome AF: 0.00570

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00782

Gnomad4 OTH exome AF: 0.00701

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0223 AC: 1113 AN: 49934 Hom.: 0 Cov.: 0 AF XY: 0.0234 AC XY: 548 AN XY: 23428

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.0208

Gnomad4 ASJ AF: 0.0140

Gnomad4 EAS AF: 0.0271

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.0288

Gnomad4 OTH AF: 0.0282

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Seizures, benign familial infantile, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.17
DANN	Benign	0.36

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: rs886054990; hg19: chr2-166150549;