2-165294039-G-A

Variant names:

• chr2-165294039-G-A
• rs886054990
• ENST00000283256.10:c.-148G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000283256.10(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 ENST00000283256.10 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.385
• 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: Likely_benign. The variant received -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1734G>A		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1734G>A		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	ENST00000283256.10	c.-148G>A		5_prime_UTR_variant	Exon 1 of 27	1		ENSP00000283256.6
SCN2A	ENST00000375437.7	c.-51-1734G>A		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1734G>A		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1734G>A		intron_variant	Intron 1 of 10	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 1111 AN: 49938 Hom.: 0 Cov.: 0

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00161 AC: 8 AN: 4964

American (AMR) AF: 0.0140 AC: 4 AN: 286

Ashkenazi Jewish (ASJ) AF: 0.00267 AC: 4 AN: 1498

East Asian (EAS) AF: 0.00893 AC: 8 AN: 896

South Asian (SAS) AF: 0.00570 AC: 25 AN: 4388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 60

Middle Eastern (MID) AF: 0.00431 AC: 2 AN: 464

European-Non Finnish (NFE) AF: 0.00782 AC: 1557 AN: 199060

Other (OTH) AF: 0.00701 AC: 50 AN: 7128

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0153 AC: 251 AN: 16368

American (AMR) AF: 0.0208 AC: 86 AN: 4140

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 21 AN: 1502

East Asian (EAS) AF: 0.0271 AC: 33 AN: 1218

South Asian (SAS) AF: 0.0184 AC: 27 AN: 1466

European-Finnish (FIN) AF: 0.0110 AC: 18 AN: 1630

Middle Eastern (MID) AF: 0.0213 AC: 2 AN: 94

European-Non Finnish (NFE) AF: 0.0288 AC: 649 AN: 22560

Other (OTH) AF: 0.0282 AC: 19 AN: 674

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Seizures, benign familial infantile, 3 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.39
PromoterAI		-0.014	Neutral

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: rs886054990; hg19: chr2-166150549;