2-165294010-T-TAAA

Variant names:

• chr2-165294010-T-TAAA
• rs67417831
• NM_001040142.2:c.-51-1737_-51-1735dupAAA

Variant summary

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

The NM_001040142.2(SCN2A):​c.-51-1737_-51-1735dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (395 hom., cov: 0)
  • Exomes 𝑓: 0.058 (50 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.292
• 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: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1737_-51-1735dupAAA		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1737_-51-1735dupAAA		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.-51-1763_-51-1762insAAA		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1763_-51-1762insAAA		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1763_-51-1762insAAA		intron_variant	Intron 1 of 10	1		ENSP00000406454.2
SCN2A	ENST00000283256.10	c.-177_-176insAAA		upstream_gene_variant		1		ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.0699 AC: 3908 AN: 55916 Hom.: 395 Cov.: 0

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.00862

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0874

Gnomad OTH AF: 0.0584

GnomAD4 exome AF: 0.0576 AC: 5443 AN: 94492 Hom.: 50 Cov.: 0 AF XY: 0.0575 AC XY: 2607 AN XY: 45348

African (AFR) AF: 0.0181 AC: 49 AN: 2702

American (AMR) AF: 0.0313 AC: 5 AN: 160

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 17 AN: 748

East Asian (EAS) AF: 0.0315 AC: 14 AN: 444

South Asian (SAS) AF: 0.0276 AC: 59 AN: 2140

European-Finnish (FIN) AF: 0.119 AC: 5 AN: 42

Middle Eastern (MID) AF: 0.0294 AC: 7 AN: 238

European-Non Finnish (NFE) AF: 0.0605 AC: 5117 AN: 84616

Other (OTH) AF: 0.0500 AC: 170 AN: 3402

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0699 AC: 3908 AN: 55926 Hom.: 395 Cov.: 0 AF XY: 0.0680 AC XY: 1656 AN XY: 24340

African (AFR) AF: 0.0466 AC: 633 AN: 13590

American (AMR) AF: 0.0386 AC: 130 AN: 3364

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 74 AN: 1980

East Asian (EAS) AF: 0.00862 AC: 13 AN: 1508

South Asian (SAS) AF: 0.0219 AC: 19 AN: 866

European-Finnish (FIN) AF: 0.105 AC: 31 AN: 296

Middle Eastern (MID) AF: 0.0870 AC: 4 AN: 46

European-Non Finnish (NFE) AF: 0.0874 AC: 2895 AN: 33132

Other (OTH) AF: 0.0584 AC: 37 AN: 634

Alfa AF: 0.00 Hom.: 0

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		0.29
Mutation Taster		=100/0	polymorphism (auto)

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;