2-165294010-T-TAA

Position:

• chr2-165294010-T-TAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001040142.2(SCN2A):​c.-51-1736_-51-1735dup variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.31 (3463 hom., cov: 0)
  • Exomes 𝑓: 0.058 (51 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.292

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.-51-1736_-51-1735dup		intron_variant		ENST00000375437.7
SCN2A	NM_001371246.1	c.-51-1736_-51-1735dup		intron_variant		ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.-51-1736_-51-1735dup		intron_variant		5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.-51-1736_-51-1735dup		intron_variant		5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 17586 AN: 56108 Hom.: 3463 Cov.: 0

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.0580 AC: 5485 AN: 94626 Hom.: 51 Cov.: 0 AF XY: 0.0597 AC XY: 2710 AN XY: 45412

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.0253

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.0438

Gnomad4 FIN exome AF: 0.0952

Gnomad4 NFE exome AF: 0.0604

Gnomad4 OTH exome AF: 0.0495

GnomAD4 genome AF: 0.313 AC: 17586 AN: 56118 Hom.: 3463 Cov.: 0 AF XY: 0.300 AC XY: 7337 AN XY: 24424

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.374

Gnomad4 OTH AF: 0.308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Early Infantile Epileptic Encephalopathy, Autosomal Dominant Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Seizures, benign familial infantile, 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs67417831; hg19: chr2-166150520;