chr12-51705503-G-C

Position:

• chr12-51705503-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The ENST00000354534.11(SCN8A):​c.1221G>C​(p.Leu407Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L407M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A ENST00000354534.11 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.91

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000354534.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51705501-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1221G>C	p.Leu407Phe	missense_variant	10/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1221G>C	p.Leu407Phe	missense_variant	10/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1221G>C	p.Leu407Phe	missense_variant	10/26		NP_001171455.1
SCN8A	NM_001369788.1	c.1221G>C	p.Leu407Phe	missense_variant	10/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1221G>C	p.Leu407Phe	missense_variant	10/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.1221G>C	p.Leu407Phe	missense_variant	10/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H;H;H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	.;D;D;D;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;D;D;D;.;.;.
Sift4G	Uncertain	0.012	.;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;D;.;.
Vest4		0.89, 0.91, 0.91, 0.89
MutPred		0.68		Gain of catalytic residue at A408 (P = 0.2423);Gain of catalytic residue at A408 (P = 0.2423);Gain of catalytic residue at A408 (P = 0.2423);Gain of catalytic residue at A408 (P = 0.2423);Gain of catalytic residue at A408 (P = 0.2423);Gain of catalytic residue at A408 (P = 0.2423);.;
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.91
gMVP		0.99

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: rs879255698; hg19: chr12-52099287;