rs905574009

chr12-51721870-G-Achr12-51721870-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_014191.4(SCN8A):c.1960G>A(p.Gly654Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.58

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN8A
• BP6: Variant 12-51721870-G-A is Benign according to our data. Variant chr12-51721870-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450870.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.1960G>A	p.Gly654Ser	missense_variant	12/27	ENST00000627620.5
SCN8A	NM_014191.4	c.1960G>A	p.Gly654Ser	missense_variant	12/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.1960G>A	p.Gly654Ser	missense_variant	12/26
SCN8A	NM_001369788.1	c.1960G>A	p.Gly654Ser	missense_variant	12/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.1960G>A	p.Gly654Ser	missense_variant	12/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.1960G>A	p.Gly654Ser	missense_variant	12/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000426 AC: 1 AN: 234482 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129122

Gnomad AFR exome AF: 0.0000687

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000138 AC: 2 AN: 1449858 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721730

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2023

Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be in the cytoplasmic loop between the first and second homologous domains; This variant is associated with the following publications: (PMID: 30653559) -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
Polyphen		0.99, 0.066	.;D;.;.;B;.;.
Vest4		0.86, 0.84, 0.85, 0.88, 0.95
MutPred		0.36		Gain of phosphorylation at G654 (P = 0.0767);Gain of phosphorylation at G654 (P = 0.0767);Gain of phosphorylation at G654 (P = 0.0767);Gain of phosphorylation at G654 (P = 0.0767);Gain of phosphorylation at G654 (P = 0.0767);Gain of phosphorylation at G654 (P = 0.0767);.;
MVP		0.62
MPC		1.1
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.22
gMVP		0.74

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: rs905574009; hg19: chr12-52115654;