2-165294039-G-C

Variant names:

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

Variant summary

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

The ENST00000283256.10(SCN2A):​c.-148G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000058 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SCN2A ENST00000283256.10 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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=-0.89).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000582 AC: 3 AN: 51576 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 25 AN: 223610 Hom.: 0 Cov.: 0 AF XY: 0.000114 AC XY: 12 AN XY: 105122

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

African (AFR) AF: 0.00 AC: 0 AN: 5010

American (AMR) AF: 0.00 AC: 0 AN: 294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1518

East Asian (EAS) AF: 0.00 AC: 0 AN: 914

South Asian (SAS) AF: 0.000223 AC: 1 AN: 4478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 62

Middle Eastern (MID) AF: 0.00213 AC: 1 AN: 470

European-Non Finnish (NFE) AF: 0.0000983 AC: 20 AN: 203552

Other (OTH) AF: 0.000410 AC: 3 AN: 7312

⚠️ 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 AF: 0.0000582 AC: 3 AN: 51576 Hom.: 0 Cov.: 0 AF XY: 0.0000829 AC XY: 2 AN XY: 24136

African (AFR) AF: 0.00 AC: 0 AN: 16712

American (AMR) AF: 0.00 AC: 0 AN: 4222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1546

East Asian (EAS) AF: 0.00 AC: 0 AN: 1268

South Asian (SAS) AF: 0.00 AC: 0 AN: 1518

European-Finnish (FIN) AF: 0.00182 AC: 3 AN: 1652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 106

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 23578

Other (OTH) AF: 0.00 AC: 0 AN: 680

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.18
DANN	Benign	0.32
PhyloP100		-0.39
PromoterAI		-0.013	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;