rs1553463594

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1PM1PM2PP2PP3PP5_Moderate

The NM_001040142.2(SCN2A):c.5308A>C(p.Met1770Leu) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.19

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1

Transcript NM_001040142.2 (SCN2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a repeat IV (size 298) in uniprot entity SCN2A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001040142.2

PM2

Very rare variant in population databases, with high coverage;

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 seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

PP5

Variant 2-165389114-A-C is Pathogenic according to our data. Variant chr2-165389114-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1325039.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 link	c.5308A>C	p.Met1770Leu	missense_variant	Exon 27 of 27	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.5308A>C	p.Met1770Leu	missense_variant	Exon 27 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2A	ENST00000375437.7 link	c.5308A>C	p.Met1770Leu	missense_variant	Exon 27 of 27	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.5308A>C	p.Met1770Leu	missense_variant	Exon 27 of 27	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000283256.10 link	c.5308A>C	p.Met1770Leu	missense_variant	Exon 27 of 27	1		ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 11

Pathogenic:1

Jan 08, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001325039). A different missense change at the same codon (p.Met1770Val) has been reported to be associated with SCN2A-related disorder (PMID: 29455050). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1

Jul 08, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.90

D;.;T;.;D;D;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;.;D;.;.;.;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.77

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

0.63

N;N;.;N;N;N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.7

D;.;.;.;.;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.017

D;.;.;.;.;D;D

Sift4G

Uncertain

0.020

D;.;.;D;.;D;D

Polyphen

0.0

B;B;.;B;B;B;B

Vest4

0.78

MutPred

0.70

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

1.0

ClinPred

0.91

GERP RS

5.7

Varity_R

0.80

gMVP

0.98

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over