chr2-165294040-A-AAATT

Position:

• chr2-165294040-A-AAATT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000283256(SCN2A):​c.-147_-146insAATT 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 0.00073 (0 hom., cov: 11)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SCN2A ENST00000283256 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.275

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000734 (76/103550) while in subpopulation NFE AF= 0.00101 (53/52458). AF 95% confidence interval is 0.000793. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 11. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1733_-51-1732insAATT		intron_variant		ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1733_-51-1732insAATT		intron_variant		ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000283256	c.-147_-146insAATT		5_prime_UTR_variant	1/27	1		ENSP00000283256.6
SCN2A	ENST00000375437.7	c.-51-1733_-51-1732insAATT		intron_variant		5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1733_-51-1732insAATT		intron_variant		5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1733_-51-1732insAATT		intron_variant		1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.000734 AC: 76 AN: 103514 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000797

Gnomad ASJ AF: 0.000380

Gnomad EAS AF: 0.000905

Gnomad SAS AF: 0.000341

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00149

GnomAD4 exome AF: 0.0000399 AC: 21 AN: 526586 Hom.: 0 Cov.: 0 AF XY: 0.0000286 AC XY: 7 AN XY: 244830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000415

Gnomad4 OTH exome AF: 0.0000580

GnomAD4 genome AF: 0.000734 AC: 76 AN: 103550 Hom.: 0 Cov.: 11 AF XY: 0.000856 AC XY: 41 AN XY: 47874

Gnomad4 AFR AF: 0.000325

Gnomad4 AMR AF: 0.000795

Gnomad4 ASJ AF: 0.000380

Gnomad4 EAS AF: 0.000906

Gnomad4 SAS AF: 0.000342

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00148

Alfa AF: 0.00345 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Early Infantile Epileptic Encephalopathy, Autosomal Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Seizures, benign familial infantile, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs780674346; hg19: chr2-166150550;