rs12301486

Positions:

chr12-51794625-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001330260.2(SCN8A):c.4779C>T(p.Val1593Val) 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_001330260.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.984

Variant links:

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]

SCN8A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

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. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1916 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2 linkuse as main transcript	c.4779C>T	p.Val1593Val	synonymous_variant	26/27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 linkuse as main transcript	c.4779C>T	p.Val1593Val	synonymous_variant	26/27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 linkuse as main transcript	c.4656C>T	p.Val1552Val	synonymous_variant	25/26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 linkuse as main transcript	c.4656C>T	p.Val1552Val	synonymous_variant	25/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.4779C>T	p.Val1593Val	synonymous_variant	26/27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.4779C>T	p.Val1593Val	synonymous_variant	26/27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 linkuse as main transcript	c.4812C>T	p.Val1604Val	synonymous_variant	25/26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 linkuse as main transcript	c.4656C>T	p.Val1552Val	synonymous_variant	24/25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1913

AN:

152122

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00321

AC XY:

434

AN XY:

135066

show subpopulations

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.:

Cov.:

AF XY:

0.00190

AC XY:

1384

AN XY:

727078

show subpopulations

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.:

Cov.:

AF XY:

0.0118

AC XY:

878

AN XY:

74436

show subpopulations

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.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	Athena Diagnostics	Dec 02, 2024	- -
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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over