2-165294040-A-ATT

Variant names:

• chr2-165294040-A-ATT
• rs1553563950
• ENST00000480032.4:n.9_10dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000283256.10(SCN2A):​c.-135_-134dupTT 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 0.21 (2525 hom., cov: 11)
  • Exomes 𝑓: 0.23 (4158 hom.)
• Consequence: SCN2A ENST00000283256.10 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1721_-51-1720dupTT		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1721_-51-1720dupTT		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.-135_-134dupTT		5_prime_UTR_variant	Exon 1 of 27	1		ENSP00000283256.6
SCN2A	ENST00000375437.7	c.-51-1721_-51-1720dupTT		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1721_-51-1720dupTT		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1721_-51-1720dupTT		intron_variant	Intron 1 of 10	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.209 AC: 21599 AN: 103568 Hom.: 2519 Cov.: 11

Gnomad AFR AF: 0.0898

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.0988

Gnomad MID AF: 0.0691

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.233 AC: 120560 AN: 516672 Hom.: 4158 Cov.: 0 AF XY: 0.234 AC XY: 56268 AN XY: 240180

African (AFR) AF: 0.0742 AC: 720 AN: 9702

American (AMR) AF: 0.284 AC: 185 AN: 652

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 451 AN: 3044

East Asian (EAS) AF: 0.290 AC: 691 AN: 2384

South Asian (SAS) AF: 0.202 AC: 2063 AN: 10236

European-Finnish (FIN) AF: 0.311 AC: 56 AN: 180

Middle Eastern (MID) AF: 0.153 AC: 138 AN: 904

European-Non Finnish (NFE) AF: 0.238 AC: 112559 AN: 472622

Other (OTH) AF: 0.218 AC: 3697 AN: 16948

GnomAD4 genome AF: 0.209 AC: 21614 AN: 103602 Hom.: 2525 Cov.: 11 AF XY: 0.198 AC XY: 9490 AN XY: 47888

African (AFR) AF: 0.0898 AC: 2486 AN: 27682

American (AMR) AF: 0.261 AC: 2296 AN: 8806

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 407 AN: 2630

East Asian (EAS) AF: 0.342 AC: 1130 AN: 3308

South Asian (SAS) AF: 0.189 AC: 553 AN: 2926

European-Finnish (FIN) AF: 0.0988 AC: 341 AN: 3452

Middle Eastern (MID) AF: 0.0739 AC: 13 AN: 176

European-Non Finnish (NFE) AF: 0.263 AC: 13829 AN: 52548

Other (OTH) AF: 0.220 AC: 297 AN: 1348

Alfa AF: 0.0944 Hom.: 203

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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		0.28
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1553563950; hg19: chr2-166150550;