12-51807365-G-C

Position:

• chr12-51807365-G-C

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.5879G>C​(p.Arg1960Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1960Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.87

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 10.436 (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=0.19908357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.5879G>C	p.Arg1960Pro	missense_variant	27/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.5879G>C	p.Arg1960Pro	missense_variant	27/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.5756G>C	p.Arg1919Pro	missense_variant	26/26		NP_001171455.1
SCN8A	NM_001369788.1	c.5756G>C	p.Arg1919Pro	missense_variant	26/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.5879G>C	p.Arg1960Pro	missense_variant	27/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.5879G>C	p.Arg1960Pro	missense_variant	27/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.5912G>C	p.Arg1971Pro	missense_variant	26/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.5756G>C	p.Arg1919Pro	missense_variant	25/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461342 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726918

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T;.;.;.;.
Eigen	Benign	0.055
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.34	N;.;.;.;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N;N;.;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.010	D;D;.;.;.
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.47	P;.;.;.;.
Vest4		0.14
MutPred		0.28		Gain of loop (P = 3e-04);.;.;.;Gain of loop (P = 3e-04);
MVP		0.82
MPC		2.4
ClinPred		0.83	D
GERP RS		4.9
Varity_R		0.59
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369346315; hg19: chr12-52201149; COSMIC: COSV61989024; COSMIC: COSV61989024;