chr12-51706525-A-C

Variant names:

• chr12-51706525-A-C
• rs769520392
• NM_001330260.2:c.1445A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001330260.2(SCN8A):​c.1445A>C​(p.Lys482Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,420 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1445A>C	p.Lys482Thr	missense_variant	Exon 11 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1445A>C	p.Lys482Thr	missense_variant	Exon 11 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1445A>C	p.Lys482Thr	missense_variant	Exon 11 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.1445A>C	p.Lys482Thr	missense_variant	Exon 11 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1445A>C	p.Lys482Thr	missense_variant	Exon 11 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1445A>C	p.Lys482Thr	missense_variant	Exon 11 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.1445A>C	p.Lys482Thr	missense_variant	Exon 10 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1445A>C	p.Lys482Thr	missense_variant	Exon 10 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000429 AC: 1 AN: 233330 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126278

Gnomad AFR exome AF: 0.00

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: 0.00000953

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453420 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722054

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;D;.;.;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.8	.;M;M;M;M;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.1	.;D;D;D;.;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.049	.;D;D;D;.;.;.
Sift4G	Benign	0.46	.;T;T;T;T;T;T
Polyphen		0.99, 0.99	.;D;.;.;D;.;.
Vest4		0.52, 0.47, 0.52, 0.50, 0.55
MutPred		0.32		Gain of phosphorylation at K482 (P = 0.023);Gain of phosphorylation at K482 (P = 0.023);Gain of phosphorylation at K482 (P = 0.023);Gain of phosphorylation at K482 (P = 0.023);Gain of phosphorylation at K482 (P = 0.023);Gain of phosphorylation at K482 (P = 0.023);.;
MVP		0.84
MPC		2.3
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.44
gMVP		0.54

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: rs769520392; hg19: chr12-52100309;