rs1555225784

chr12-51765689-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_014191.4(SCN8A):c.2563G>A(p.Ala855Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. A855G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.15

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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_014191.4
• PP2: Missense variant where missense usually causes diseases, SCN8A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.2563G>A	p.Ala855Thr	missense_variant	16/27	ENST00000627620.5
SCN8A	NM_014191.4	c.2563G>A	p.Ala855Thr	missense_variant	16/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.2563G>A	p.Ala855Thr	missense_variant	16/26
SCN8A	NM_001369788.1	c.2563G>A	p.Ala855Thr	missense_variant	16/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.2563G>A	p.Ala855Thr	missense_variant	16/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.2563G>A	p.Ala855Thr	missense_variant	16/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1430056 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 707112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 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 expected to disrupt SCN8A protein function. ClinVar contains an entry for this variant (Variation ID: 523504). 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 alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 855 of the SCN8A protein (p.Ala855Thr). -

Intellectual disability, moderate Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L;L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	D;D;D;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.014	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.59
MutPred		0.64		Loss of ubiquitination at K853 (P = 0.0997);Loss of ubiquitination at K853 (P = 0.0997);Loss of ubiquitination at K853 (P = 0.0997);.;Loss of ubiquitination at K853 (P = 0.0997);
MVP		0.98
MPC		3.1
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.84
gMVP		0.97

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: rs1555225784; hg19: chr12-52159473;