NM_001040142.2:c.-51-1745_-51-1735delAAAAAAAAAAA

Variant names:

• chr2-165294010-TAAAAAAAAAAA-T
• rs67417831
• NM_001040142.2:c.-51-1745_-51-1735delAAAAAAAAAAA

Variant summary

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

The NM_001040142.2(SCN2A):​c.-51-1745_-51-1735delAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000463 in 151,042 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 0.00054 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00042 (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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000536 (30/55920) while in subpopulation EAS AF = 0.00133 (2/1508). AF 95% confidence interval is 0.000243. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1745_-51-1735delAAAAAAAAAAA		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1745_-51-1735delAAAAAAAAAAA		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_-51-1752delAAAAAAAAAAA		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1762_-51-1752delAAAAAAAAAAA		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1762_-51-1752delAAAAAAAAAAA		intron_variant	Intron 1 of 10	1		ENSP00000406454.2
SCN2A	ENST00000283256.10	c.-176_-166delAAAAAAAAAAA		upstream_gene_variant		1		ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.000537 AC: 30 AN: 55910 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000894

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00133

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000302

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000421 AC: 40 AN: 95122 Hom.: 0 AF XY: 0.000460 AC XY: 21 AN XY: 45646

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

American (AMR) AF: 0.0125 AC: 2 AN: 160

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

East Asian (EAS) AF: 0.00225 AC: 1 AN: 444

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

European-Finnish (FIN) AF: 0.0238 AC: 1 AN: 42

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

European-Non Finnish (NFE) AF: 0.000352 AC: 30 AN: 85206

Other (OTH) AF: 0.00117 AC: 4 AN: 3420

GnomAD4 genome AF: 0.000536 AC: 30 AN: 55920 Hom.: 0 Cov.: 0 AF XY: 0.000822 AC XY: 20 AN XY: 24330

African (AFR) AF: 0.0000735 AC: 1 AN: 13604

American (AMR) AF: 0.000893 AC: 3 AN: 3360

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

East Asian (EAS) AF: 0.00133 AC: 2 AN: 1508

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

European-Finnish (FIN) AF: 0.0470 AC: 14 AN: 298

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

European-Non Finnish (NFE) AF: 0.000302 AC: 10 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		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;