rs1555229539

Positions:

• chr12-51794588-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 9P and 2B. PM1 PM2 PP2 PP3_Strong BP6_Moderate

The NM_001330260.2(SCN8A):​c.4742T>A​(p.Phe1581Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.02

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 7 ACMG points.

• PM1: In a repeat IV (size 297) in uniprot entity SCN8A_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_001330260.2
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• BP6: Variant 12-51794588-T-A is Benign according to our data. Variant chr12-51794588-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 530596.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4742T>A	p.Phe1581Tyr	missense_variant	26/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4742T>A	p.Phe1581Tyr	missense_variant	26/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4619T>A	p.Phe1540Tyr	missense_variant	25/26		NP_001171455.1
SCN8A	NM_001369788.1	c.4619T>A	p.Phe1540Tyr	missense_variant	25/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4742T>A	p.Phe1581Tyr	missense_variant	26/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4742T>A	p.Phe1581Tyr	missense_variant	26/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4775T>A	p.Phe1592Tyr	missense_variant	25/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4619T>A	p.Phe1540Tyr	missense_variant	24/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.;.;.;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;D;N;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.79
MutPred		0.80		Gain of catalytic residue at L1576 (P = 0.1591);.;.;.;Gain of catalytic residue at L1576 (P = 0.1591);
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.86
gMVP		0.93

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: rs1555229539; hg19: chr12-52188372;