chr2-165354645-GA-G

Variant names:

• chr2-165354645-GA-G
• rs587780450
• NM_001040142.2:c.3374delA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001040142.2(SCN2A):​c.3374delA​(p.Glu1125GlyfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.20
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165354645-GA-G is Pathogenic according to our data. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165354645-GA-G is described in CliVar as Pathogenic. Clinvar id is 130220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.3374delA	p.Glu1125GlyfsTer11	frameshift_variant	Exon 17 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.3374delA	p.Glu1125GlyfsTer11	frameshift_variant	Exon 17 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.3374delA	p.Glu1125GlyfsTer11	frameshift_variant	Exon 17 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.3374delA	p.Glu1125GlyfsTer11	frameshift_variant	Exon 17 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.3374delA	p.Glu1125GlyfsTer11	frameshift_variant	Exon 17 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Seizures, benign familial infantile, 3 Pathogenic:1

Dec 10, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Complex neurodevelopmental disorder Pathogenic:1

Jul 14, 2016

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-07-14 and interpreted as Pathogenic. Variant was initially reported on 2013-12-11 by GTR ID of laboratory name 1238. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587780450; hg19: chr2-166211155;