12-51721729-G-T

Variant names:

• chr12-51721729-G-T
• rs367949317
• NM_001330260.2:c.1819G>T

Variant summary

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

The NM_001330260.2(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_001330260.2 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 the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.436 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1819G>T	p.Ala607Ser	missense_variant	Exon 12 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1819G>T	p.Ala607Ser	missense_variant	Exon 12 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1819G>T	p.Ala607Ser	missense_variant	Exon 12 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.1819G>T	p.Ala607Ser	missense_variant	Exon 12 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1819G>T	p.Ala607Ser	missense_variant	Exon 12 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1819G>T	p.Ala607Ser	missense_variant	Exon 12 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.1819G>T	p.Ala607Ser	missense_variant	Exon 11 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1819G>T	p.Ala607Ser	missense_variant	Exon 11 of 25	1		ENSP00000347255.4

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;.
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;