rs12301486

chr12-51794625-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_014191.4(SCN8A):c.4779C>T(p.Val1593=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,826 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (53 hom.)
• Consequence: SCN8A NM_014191.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.984

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 Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 12-51794625-C-T is Benign according to our data. Variant chr12-51794625-C-T is described in ClinVar as [Benign]. Clinvar id is 130250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51794625-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1916/152240) while in subpopulation AFR AF= 0.0409 (1698/41514). AF 95% confidence interval is 0.0393. There are 33 homozygotes in gnomad4. There are 878 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1913 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4779C>T	p.Val1593=	synonymous_variant	26/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4779C>T	p.Val1593=	synonymous_variant	26/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.4656C>T	p.Val1552=	synonymous_variant	25/26
SCN8A	NM_001369788.1	c.4656C>T	p.Val1552=	synonymous_variant	25/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.4779C>T	p.Val1593=	synonymous_variant	26/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.4779C>T	p.Val1593=	synonymous_variant	26/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1913 AN: 152122 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00392 AC: 975 AN: 248918 Hom.: 18 AF XY: 0.00321 AC XY: 434 AN XY: 135066

Gnomad AFR exome AF: 0.0451

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00209 AC: 3055 AN: 1461586 Hom.: 53 Cov.: 32 AF XY: 0.00190 AC XY: 1384 AN XY: 727078

Gnomad4 AFR exome AF: 0.0493

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000773

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.0126 AC: 1916 AN: 152240 Hom.: 33 Cov.: 32 AF XY: 0.0118 AC XY: 878 AN XY: 74436

Gnomad4 AFR AF: 0.0409

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00560 Hom.: 8

Bravo AF: 0.0150

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	12
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12301486; hg19: chr12-52188409;