2-165294010-TAAAA-T

Variant names:

• chr2-165294010-TAAAA-T
• rs67417831
• NM_001040142.2:c.-51-1738_-51-1735delAAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001040142.2(SCN2A):​c.-51-1738_-51-1735delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 150,560 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 0)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.311
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000322 (18/55918) while in subpopulation AFR AF = 0.00118 (16/13602). AF 95% confidence interval is 0.000737. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1738_-51-1735delAAAA		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1738_-51-1735delAAAA		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	ENST00000375437.7	c.-51-1762_-51-1759delAAAA		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1762_-51-1759delAAAA		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1762_-51-1759delAAAA		intron_variant	Intron 1 of 10	1		ENSP00000406454.2
SCN2A	ENST00000283256.10	c.-176_-173delAAAA		upstream_gene_variant		1		ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 18 AN: 55908 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000298

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000302

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0206 AC: 1949 AN: 94642 Hom.: 0 AF XY: 0.0196 AC XY: 889 AN XY: 45392

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

African (AFR) AF: 0.0390 AC: 105 AN: 2690

American (AMR) AF: 0.0190 AC: 3 AN: 158

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 25 AN: 744

East Asian (EAS) AF: 0.0226 AC: 10 AN: 442

South Asian (SAS) AF: 0.0130 AC: 28 AN: 2156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42

Middle Eastern (MID) AF: 0.00847 AC: 2 AN: 236

European-Non Finnish (NFE) AF: 0.0201 AC: 1703 AN: 84780

Other (OTH) AF: 0.0215 AC: 73 AN: 3394

⚠️ 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: 0.000322 AC: 18 AN: 55918 Hom.: 0 Cov.: 0 AF XY: 0.000329 AC XY: 8 AN XY: 24330

African (AFR) AF: 0.00118 AC: 16 AN: 13602

American (AMR) AF: 0.000298 AC: 1 AN: 3360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1982

East Asian (EAS) AF: 0.00 AC: 0 AN: 1508

South Asian (SAS) AF: 0.00 AC: 0 AN: 864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 46

European-Non Finnish (NFE) AF: 0.0000302 AC: 1 AN: 33120

Other (OTH) AF: 0.00 AC: 0 AN: 634

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31
Mutation Taster		=99/1	polymorphism

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: rs67417831; hg19: chr2-166150520;