rs371766742

chr12-51807281-G-Achr12-51807281-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_014191.4(SCN8A):c.5795G>A(p.Arg1932Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. R1932P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN8A
• BP4: Computational evidence support a benign effect (MetaRNN=0.07247245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.5795G>A	p.Arg1932Gln	missense_variant	27/27	ENST00000627620.5
SCN8A	NM_014191.4	c.5795G>A	p.Arg1932Gln	missense_variant	27/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.5672G>A	p.Arg1891Gln	missense_variant	26/26
SCN8A	NM_001369788.1	c.5672G>A	p.Arg1891Gln	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.5795G>A	p.Arg1932Gln	missense_variant	27/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.5795G>A	p.Arg1932Gln	missense_variant	27/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249066 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135140

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461694 Hom.: 1 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Invitae

Nov 14, 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN8A protein function. ClinVar contains an entry for this variant (Variation ID: 1516886). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is present in population databases (rs371766742, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1932 of the SCN8A protein (p.Arg1932Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.26	T;.;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.072	T;T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	-0.23	N;.;.;.;N
MutationTaster	Benign	0.71	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.040	N;N;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.28	T;T;.;.;.
Sift4G	Benign	0.56	T;T;T;T;T
Polyphen		0.0020	B;.;.;.;.
Vest4		0.065
MVP		0.68
MPC		1.2
ClinPred		0.093	T
GERP RS		4.2
Varity_R		0.041
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs371766742; hg19: chr12-52201065; COSMIC: COSV61989360; COSMIC: COSV61989360;