2-165294038-AG-A

Variant names:

• chr2-165294038-AG-A
• rs886054994
• ENST00000283256.10:c.-148delG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000283256.10(SCN2A):​c.-148delG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN2A ENST00000283256.10 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 90 AN: 122232 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000469

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000447

Gnomad ASJ AF: 0.00239

Gnomad EAS AF: 0.000835

Gnomad SAS AF: 0.00219

Gnomad FIN AF: 0.000142

Gnomad MID AF: 0.00769

Gnomad NFE AF: 0.000824

Gnomad OTH AF: 0.000625

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000236 AC: 160 AN: 677174 Hom.: 0 Cov.: 0 AF XY: 0.000219 AC XY: 69 AN XY: 314528

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

African (AFR) AF: 0.000403 AC: 5 AN: 12410

American (AMR) AF: 0.00 AC: 0 AN: 758

Ashkenazi Jewish (ASJ) AF: 0.000250 AC: 1 AN: 3994

East Asian (EAS) AF: 0.000687 AC: 2 AN: 2912

South Asian (SAS) AF: 0.000228 AC: 3 AN: 13132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1264

European-Non Finnish (NFE) AF: 0.000232 AC: 144 AN: 620462

Other (OTH) AF: 0.000227 AC: 5 AN: 22008

⚠️ 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: 0.000744 AC: 91 AN: 122274 Hom.: 0 Cov.: 0 AF XY: 0.000888 AC XY: 52 AN XY: 58578

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

African (AFR) AF: 0.000497 AC: 17 AN: 34188

American (AMR) AF: 0.000447 AC: 5 AN: 11190

Ashkenazi Jewish (ASJ) AF: 0.00239 AC: 7 AN: 2932

East Asian (EAS) AF: 0.000838 AC: 3 AN: 3582

South Asian (SAS) AF: 0.00219 AC: 8 AN: 3650

European-Finnish (FIN) AF: 0.000142 AC: 1 AN: 7052

Middle Eastern (MID) AF: 0.00833 AC: 2 AN: 240

European-Non Finnish (NFE) AF: 0.000824 AC: 47 AN: 57068

Other (OTH) AF: 0.000622 AC: 1 AN: 1608

⚠️ 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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Early Infantile Epileptic Encephalopathy, Autosomal Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizures, benign familial infantile, 3 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39

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: rs886054994; hg19: chr2-166150548;