rs796053124

Variant names:

• chr2-165354232-G-A
• rs796053124
• NM_001040142.2:c.2960G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-165354232-G-A
• chr2-165354232-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_001040142.2(SCN2A):​c.2960G>A​(p.Ser987Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S987I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 10.0
• 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 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-165354232-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 206978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the SCN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 362 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Trascript score misZ: 8.7114 (above the threshold of 3.09). GenCC associations: The gene is linked to genetic developmental and epileptic encephalopathy, episodic ataxia, type 9, seizures, benign familial infantile, 3, complex neurodevelopmental disorder, benign familial neonatal-infantile seizures, Dravet syndrome, infantile spasms, developmental and epileptic encephalopathy, 11, intellectual disability, benign familial infantile epilepsy, malignant migrating partial seizures of infancy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 2-165354232-G-A is Pathogenic according to our data. Variant chr2-165354232-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1203296.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.2960G>A	p.Ser987Asn	missense_variant	Exon 17 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.2960G>A	p.Ser987Asn	missense_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.2960G>A	p.Ser987Asn	missense_variant	Exon 17 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.2960G>A	p.Ser987Asn	missense_variant	Exon 17 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.2960G>A	p.Ser987Asn	missense_variant	Exon 17 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 30, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This substitution is predicted to be within the cytoplasmic loop between the second and third homologous domains; Has not been previously published as pathogenic or benign to our knowledge -

SCN2A-related disorder Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Likely pathogenic and reported on 08-09-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;T;.;D;D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.;M;M;M;M
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D;.;.;.;.;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Benign	0.11	T;.;.;T;.;T;T
Polyphen		0.62	P;P;.;P;P;P;P
Vest4		0.55
MutPred		0.37		Loss of catalytic residue at S984 (P = 0.0867);Loss of catalytic residue at S984 (P = 0.0867);.;Loss of catalytic residue at S984 (P = 0.0867);Loss of catalytic residue at S984 (P = 0.0867);Loss of catalytic residue at S984 (P = 0.0867);Loss of catalytic residue at S984 (P = 0.0867);
MVP		0.98
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.93
gMVP		0.88
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs796053124; hg19: chr2-166210742;