rs1060501010

Variant names:

• chr12-51765753-G-A
• NM_001330260.2:c.2627G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51765753-G-A
• chr12-51765753-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001330260.2(SCN8A):​c.2627G>A​(p.Gly876Asp) 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. 12/21 in silico tools predict a damaging outcome for this variant. 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 U:1
• Conservation: PhyloP100: 8.14

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a repeat II (size 272) in uniprot entity SCN8A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 12-51765753-G-A is Pathogenic according to our data. Variant chr12-51765753-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1794012.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.2627G>A	p.Gly876Asp	missense_variant	Exon 16 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.2627G>A	p.Gly876Asp	missense_variant	Exon 16 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.2627G>A	p.Gly876Asp	missense_variant	Exon 16 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.2627G>A	p.Gly876Asp	missense_variant	Exon 16 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.2627G>A	p.Gly876Asp	missense_variant	Exon 16 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.2627G>A	p.Gly876Asp	missense_variant	Exon 16 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.2660G>A	p.Gly887Asp	missense_variant	Exon 15 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.2627G>A	p.Gly876Asp	missense_variant	Exon 15 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 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

May 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN8A c.2627G>A; p.Gly876Asp variant (ClinVar Variation ID 1794012) is reported in the literature in 2 individuals affected with epileptic encephalopathy (Peng 2022, Yang 2022). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.961). Based on available information, this variant is considered to be likely pathogenic. References: Peng BW et al. Genotype-phenotype correlations in SCN8A-related epilepsy: a cohort study of Chinese children in southern China. Brain. 2022 May 24. PMID: 35230384. Yang L et al. Use of medical exome sequencing for identification of underlying genetic defects in NICU: Experience in a cohort of 2303 neonates in China. Clin Genet. 2022 Jan. PMID: 34671977. -

Inborn genetic diseases Uncertain:1

Mar 08, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G876D variant (also known as c.2627G>A), located in coding exon 15 of the SCN8A gene, results from a G to A substitution at nucleotide position 2627. The glycine at codon 876 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;.;H
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-6.7	D;D;D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.92
MutPred		0.77		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;Gain of relative solvent accessibility (P = 0.1259);
MVP		1.0
MPC		3.7
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.99
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-52159537;