NM_001040142.2:c.-51-1747_-51-1735delAAAAAAAAAAAAA

Variant names:

• chr2-165294010-TAAAAAAAAAAAAA-T
• rs67417831
• NM_001040142.2:c.-51-1747_-51-1735delAAAAAAAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001040142.2(SCN2A):​c.-51-1747_-51-1735delAAAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 151,032 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78
• 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.

• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1747_-51-1735delAAAAAAAAAAAAA		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1747_-51-1735delAAAAAAAAAAAAA		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_-51-1750delAAAAAAAAAAAAA		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1762_-51-1750delAAAAAAAAAAAAA		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1762_-51-1750delAAAAAAAAAAAAA		intron_variant	Intron 1 of 10	1		ENSP00000406454.2
SCN2A	ENST00000283256.10	c.-176_-164delAAAAAAAAAAAAA		upstream_gene_variant		1		ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 1 AN: 55910 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000302

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000200 AC: 19 AN: 95122 Hom.: 0 AF XY: 0.000219 AC XY: 10 AN XY: 45646

African (AFR) AF: 0.000370 AC: 1 AN: 2706

American (AMR) AF: 0.00 AC: 0 AN: 160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 748

East Asian (EAS) AF: 0.00 AC: 0 AN: 442

South Asian (SAS) AF: 0.000463 AC: 1 AN: 2158

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000188 AC: 16 AN: 85208

Other (OTH) AF: 0.000292 AC: 1 AN: 3420

GnomAD4 genome AF: 0.0000179 AC: 1 AN: 55910 Hom.: 0 Cov.: 0 AF XY: 0.0000411 AC XY: 1 AN XY: 24320

African (AFR) AF: 0.00 AC: 0 AN: 13598

American (AMR) AF: 0.00 AC: 0 AN: 3356

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: 48

European-Non Finnish (NFE) AF: 0.0000302 AC: 1 AN: 33118

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		2.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs67417831; hg19: chr2-166150520;