12-51721729-G-T

Position:

• chr12-51721729-G-T

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.1819G>T​(p.Ala607Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A607T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64

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=0.19102305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.1819G>T	p.Ala607Ser	missense_variant	12/27	ENST00000627620.5
SCN8A	NM_014191.4	c.1819G>T	p.Ala607Ser	missense_variant	12/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.1819G>T	p.Ala607Ser	missense_variant	12/26
SCN8A	NM_001369788.1	c.1819G>T	p.Ala607Ser	missense_variant	12/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.1819G>T	p.Ala607Ser	missense_variant	12/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.1819G>T	p.Ala607Ser	missense_variant	12/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	.;T;.;.;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	-0.69	.;N;N;N;N;N;.
MutationTaster	Benign	0.73	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.19	.;N;N;N;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.40	.;T;T;T;.;.;.
Sift4G	Benign	0.43	.;T;T;T;T;T;T
Polyphen		0.0, 0.0040	.;B;.;.;B;.;.
Vest4		0.32, 0.33, 0.36, 0.35, 0.32
MutPred		0.25		Gain of phosphorylation at A607 (P = 0.0016);Gain of phosphorylation at A607 (P = 0.0016);Gain of phosphorylation at A607 (P = 0.0016);Gain of phosphorylation at A607 (P = 0.0016);Gain of phosphorylation at A607 (P = 0.0016);Gain of phosphorylation at A607 (P = 0.0016);.;
MVP		0.58
MPC		0.89
ClinPred		0.80	D
GERP RS		3.8
Varity_R		0.14
gMVP		0.55

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: rs367949317; hg19: chr12-52115513;