chr12-51687181-C-T

Position:

chr12-51687181-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001330260.2(SCN8A):c.576C>T(p.Asp192Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.853 in 1,612,864 control chromosomes in the GnomAD database, including 590,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 51038 hom., cov: 31)

Exomes 𝑓: 0.86 ( 539464 hom. )

Consequence

SCN8A
NM_001330260.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.821

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:

SCN8A (HGNC:):

SCN8A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-51687181-C-T is Benign according to our data. Variant chr12-51687181-C-T is described in ClinVar as [Benign]. Clinvar id is 130253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51687181-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.821 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2 linkuse as main transcript	c.576C>T	p.Asp192Asp	synonymous_variant	5/27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 linkuse as main transcript	c.576C>T	p.Asp192Asp	synonymous_variant	5/27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 linkuse as main transcript	c.576C>T	p.Asp192Asp	synonymous_variant	5/26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 linkuse as main transcript	c.576C>T	p.Asp192Asp	synonymous_variant	5/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.576C>T	p.Asp192Asp	synonymous_variant	5/27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.576C>T	p.Asp192Asp	synonymous_variant	5/27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 linkuse as main transcript	c.576C>T	p.Asp192Asp	synonymous_variant	4/26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 linkuse as main transcript	c.576C>T	p.Asp192Asp	synonymous_variant	4/25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

AF:

0.812

AC:

123333

AN:

151978

Hom.:

50974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.653

Gnomad AMI

AF:

0.922

Gnomad AMR

AF:

0.872

Gnomad ASJ

AF:

0.785

Gnomad EAS

AF:

0.993

Gnomad SAS

AF:

0.688

Gnomad FIN

AF:

0.918

Gnomad MID

AF:

0.761

Gnomad NFE

AF:

0.872

Gnomad OTH

AF:

0.831

GnomAD3 exomes

AF:

0.848

AC:

211106

AN:

249070

Hom.:

90723

AF XY:

0.838

AC XY:

113309

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.653

Gnomad AMR exome

AF:

0.918

Gnomad ASJ exome

AF:

0.805

Gnomad EAS exome

AF:

0.991

Gnomad SAS exome

AF:

0.679

Gnomad FIN exome

AF:

0.914

Gnomad NFE exome

AF:

0.866

Gnomad OTH exome

AF:

0.848

GnomAD4 exome

AF:

0.857

AC:

1251595

AN:

1460768

Hom.:

539464

Cov.:

AF XY:

0.851

AC XY:

618711

AN XY:

726702

show subpopulations

Gnomad4 AFR exome

AF:

0.645

Gnomad4 AMR exome

AF:

0.913

Gnomad4 ASJ exome

AF:

0.810

Gnomad4 EAS exome

AF:

0.995

Gnomad4 SAS exome

AF:

0.679

Gnomad4 FIN exome

AF:

0.913

Gnomad4 NFE exome

AF:

0.869

Gnomad4 OTH exome

AF:

0.846

GnomAD4 genome

AF:

0.812

AC:

123455

AN:

152096

Hom.:

51038

Cov.:

AF XY:

0.813

AC XY:

60480

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.654

Gnomad4 AMR

AF:

0.872

Gnomad4 ASJ

AF:

0.785

Gnomad4 EAS

AF:

0.993

Gnomad4 SAS

AF:

0.689

Gnomad4 FIN

AF:

0.918

Gnomad4 NFE

AF:

0.872

Gnomad4 OTH

AF:

0.833

Alfa

AF:

0.852

Hom.:

73269

Bravo

AF:

0.808

Asia WGS

AF:

0.855

AC:

2969

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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	Eurofins Ntd Llc (ga)	Oct 22, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 92% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 86. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2015

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

- -

Cognitive impairment with or without cerebellar ataxia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Seizures, benign familial infantile, 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Myoclonus, familial, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Developmental and epileptic encephalopathy, 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.9

DANN

Benign

0.89

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

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