chr12-51662853-T-G

Position:

• chr12-51662853-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014191.4(SCN8A):​c.36T>G​(p.Asp12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D12G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.397

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN8A. . Gene score misZ 0.78755 (greater than the threshold 3.09). Trascript score misZ 10.278 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11667776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.36T>G	p.Asp12Glu	missense_variant	2/27	ENST00000627620.5
SCN8A	NM_014191.4	c.36T>G	p.Asp12Glu	missense_variant	2/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.36T>G	p.Asp12Glu	missense_variant	2/26
SCN8A	NM_001369788.1	c.36T>G	p.Asp12Glu	missense_variant	2/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.36T>G	p.Asp12Glu	missense_variant	2/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.36T>G	p.Asp12Glu	missense_variant	2/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1064214). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 12 of the SCN8A protein (p.Asp12Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	.;T;.;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.71	T;T;T;.;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.4	.;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	.;N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.32	.;T;T;T;.;.
Sift4G	Benign	0.52	.;T;T;T;T;T
Polyphen		0.47	.;P;.;.;.;.
Vest4		0.12, 0.17, 0.16, 0.16, 0.17
MutPred		0.19		Gain of glycosylation at P11 (P = 0.1082);Gain of glycosylation at P11 (P = 0.1082);Gain of glycosylation at P11 (P = 0.1082);Gain of glycosylation at P11 (P = 0.1082);Gain of glycosylation at P11 (P = 0.1082);Gain of glycosylation at P11 (P = 0.1082);
MVP		0.78
MPC		0.88
ClinPred		0.14	T
GERP RS		-0.14
Varity_R		0.075
gMVP		0.60

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.

Other links and lift over

hg19: chr12-52056637;