12-51794480-C-T

Position:

• chr12-51794480-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 5P and 7B. PM1 PM2 PP2 BP4_Moderate BP6 BS2

The NM_001330260.2(SCN8A):​c.4634C>T​(p.Thr1545Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.79

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_benign. Variant got -2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2217597).
• BP6: Variant 12-51794480-C-T is Benign according to our data. Variant chr12-51794480-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548028.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4634C>T	p.Thr1545Ile	missense_variant	26/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4634C>T	p.Thr1545Ile	missense_variant	26/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4511C>T	p.Thr1504Ile	missense_variant	25/26		NP_001171455.1
SCN8A	NM_001369788.1	c.4511C>T	p.Thr1504Ile	missense_variant	25/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4634C>T	p.Thr1545Ile	missense_variant	26/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4634C>T	p.Thr1545Ile	missense_variant	26/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4667C>T	p.Thr1556Ile	missense_variant	25/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4511C>T	p.Thr1504Ile	missense_variant	24/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249220 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461712 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2017

The p.T1545I variant (also known as c.4634C>T), located in coding exon 25 of the SCN8A gene, results from a C to T substitution at nucleotide position 4634. The threonine at codon 1545 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 13;C4310728:Seizures, benign familial infantile, 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 15, 2018

- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.;.
Eigen	Benign	-0.069
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.34	N;.;.;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N;N;N;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.012	D;D;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.70	P;.;.;.;.
Vest4		0.33
MutPred		0.34		Loss of disorder (P = 0.0213);.;.;.;Loss of disorder (P = 0.0213);
MVP		0.74
MPC		1.1
ClinPred		0.41	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.66

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: rs759753811; hg19: chr12-52188264;