rs796053217

Variant names:

• chr12-51790413-A-C
• rs796053217
• NM_001330260.2:c.4435A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-51790413-A-C
• chr12-51790413-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001330260.2(SCN8A):​c.4435A>C​(p.Ile1479Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.436 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonus, familial, 2, infantile convulsions and choreoathetosis, cognitive impairment with or without cerebellar ataxia, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 13, benign familial infantile epilepsy, seizures, benign familial infantile, 5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4435A>C	p.Ile1479Leu	missense_variant	Exon 25 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4435A>C	p.Ile1479Leu	missense_variant	Exon 25 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4312A>C	p.Ile1438Leu	missense_variant	Exon 24 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.4312A>C	p.Ile1438Leu	missense_variant	Exon 24 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4435A>C	p.Ile1479Leu	missense_variant	Exon 25 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4435A>C	p.Ile1479Leu	missense_variant	Exon 25 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4468A>C	p.Ile1490Leu	missense_variant	Exon 24 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4312A>C	p.Ile1438Leu	missense_variant	Exon 23 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1479 of the SCN8A protein (p.Ile1479Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 952494). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN8A protein function with a negative predictive value of 95%. This variant disrupts the p.Ile1479 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25568300; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	0.84	L;.;.;.;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N;N;N;.;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.95	P;.;.;.;.
Vest4		0.56
MutPred		0.30		Gain of helix (P = 0.132);.;.;.;Gain of helix (P = 0.132);
MVP		0.79
MPC		1.1
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.63
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs796053217; hg19: chr12-52184197;