2-165294040-ATT-AT

Variant names:

• chr2-165294040-AT-A
• rs1553563950
• ENST00000480032.4:n.10delT

Variant summary

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

The ENST00000283256.10(SCN2A):​c.-134delT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 11)
  • Exomes 𝑓: 0.055 (2 hom.)
• Consequence: SCN2A ENST00000283256.10 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.275
• 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 = 0.0102 (1060/103632) while in subpopulation AFR AF = 0.0351 (973/27692). AF 95% confidence interval is 0.0333. There are 9 homozygotes in GnomAd4. There are 510 alleles in the male GnomAd4 subpopulation. Median coverage is 11. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1060 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1720delT		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1720delT		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.-134delT		5_prime_UTR_variant	Exon 1 of 27	1		ENSP00000283256.6
SCN2A	ENST00000375437.7	c.-51-1720delT		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1720delT		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1720delT		intron_variant	Intron 1 of 10	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1060 AN: 103596 Hom.: 9 Cov.: 11

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000380

Gnomad EAS AF: 0.000302

Gnomad SAS AF: 0.000682

Gnomad FIN AF: 0.000869

Gnomad MID AF: 0.00526

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00595

GnomAD4 exome AF: 0.0552 AC: 27259 AN: 493646 Hom.: 2 Cov.: 0 AF XY: 0.0557 AC XY: 12774 AN XY: 229386

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

African (AFR) AF: 0.113 AC: 1014 AN: 8962

American (AMR) AF: 0.0557 AC: 35 AN: 628

Ashkenazi Jewish (ASJ) AF: 0.0707 AC: 194 AN: 2744

East Asian (EAS) AF: 0.0292 AC: 68 AN: 2328

South Asian (SAS) AF: 0.0511 AC: 496 AN: 9700

European-Finnish (FIN) AF: 0.0407 AC: 7 AN: 172

Middle Eastern (MID) AF: 0.0810 AC: 69 AN: 852

European-Non Finnish (NFE) AF: 0.0541 AC: 24440 AN: 452134

Other (OTH) AF: 0.0580 AC: 936 AN: 16126

⚠️ 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: 0.0102 AC: 1060 AN: 103632 Hom.: 9 Cov.: 11 AF XY: 0.0106 AC XY: 510 AN XY: 47900

African (AFR) AF: 0.0351 AC: 973 AN: 27692

American (AMR) AF: 0.00431 AC: 38 AN: 8820

Ashkenazi Jewish (ASJ) AF: 0.000380 AC: 1 AN: 2632

East Asian (EAS) AF: 0.000302 AC: 1 AN: 3308

South Asian (SAS) AF: 0.000342 AC: 1 AN: 2928

European-Finnish (FIN) AF: 0.000869 AC: 3 AN: 3454

Middle Eastern (MID) AF: 0.00562 AC: 1 AN: 178

European-Non Finnish (NFE) AF: 0.000647 AC: 34 AN: 52540

Other (OTH) AF: 0.00593 AC: 8 AN: 1348

Alfa AF: 0.00 Hom.: 203

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28
Mutation Taster		=100/0	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: rs1553563950; hg19: chr2-166150550;