2-165294040-A-T

Variant names:

• chr2-165294040-A-T
• rs76193610
• ENST00000283256:c.-147A>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000283256(SCN2A):​c.-147A>T 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 0.00037 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00059 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN2A ENST00000283256 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.420

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000586 (308/525172) while in subpopulation AMR AF= 0.00152 (1/658). AF 95% confidence interval is 0.000632. There are 0 homozygotes in gnomad4_exome. There are 138 alleles in male gnomad4_exome subpopulation. Median coverage is 8. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 308 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1733A>T		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1733A>T		intron_variant	Intron 1 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000283256	c.-147A>T		5_prime_UTR_variant	Exon 1 of 27	1		ENSP00000283256.6
SCN2A	ENST00000375437.7	c.-51-1733A>T		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1733A>T		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1733A>T		intron_variant	Intron 1 of 10	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 38 AN: 103596 Hom.: 0 Cov.: 20 FAILED QC

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000227

Gnomad ASJ AF: 0.000380

Gnomad EAS AF: 0.000302

Gnomad SAS AF: 0.000683

Gnomad FIN AF: 0.00202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000247

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000586 AC: 308 AN: 525172 Hom.: 0 Cov.: 8 AF XY: 0.000565 AC XY: 138 AN XY: 244194

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.000980

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000676

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000551

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000367 AC: 38 AN: 103632 Hom.: 0 Cov.: 20 AF XY: 0.000438 AC XY: 21 AN XY: 47902

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000227

Gnomad4 ASJ AF: 0.000380

Gnomad4 EAS AF: 0.000302

Gnomad4 SAS AF: 0.000684

Gnomad4 FIN AF: 0.00202

Gnomad4 NFE AF: 0.000247

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Seizures, benign familial infantile, 3 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.34

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: rs76193610; hg19: chr2-166150550;