rs587780454

Variant names:

• chr12-51794620-G-A
• rs587780454
• NM_001330260.2:c.4774G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51794620-G-A
• chr12-51794620-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001330260.2(SCN8A):​c.4774G>A​(p.Val1592Ile) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:1
• Conservation: PhyloP100: 10.0

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 5 ACMG points.

• PM1: In a repeat IV (size 297) in uniprot entity SCN8A_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_001330260.2
• 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.4774G>A	p.Val1592Ile	missense_variant	Exon 26 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4774G>A	p.Val1592Ile	missense_variant	Exon 26 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4651G>A	p.Val1551Ile	missense_variant	Exon 25 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.4651G>A	p.Val1551Ile	missense_variant	Exon 25 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4774G>A	p.Val1592Ile	missense_variant	Exon 26 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4774G>A	p.Val1592Ile	missense_variant	Exon 26 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4807G>A	p.Val1603Ile	missense_variant	Exon 25 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4651G>A	p.Val1551Ile	missense_variant	Exon 24 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Pathogenic:1

Dec 28, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_MOD,PM5,PM2_SUP,PP2,PP3 -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Dec 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;.;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;.;.;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.86	N;N;N;.;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;T;.;.
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.97	D;.;.;.;.
Vest4		0.62
MutPred		0.61		Loss of catalytic residue at V1592 (P = 0.3344);.;.;.;Loss of catalytic residue at V1592 (P = 0.3344);
MVP		0.79
MPC		1.9
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.66
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780454; hg19: chr12-52188404;