chr12-51806958-C-A

Position:

chr12-51806958-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_014191.4(SCN8A):c.5472C>A(p.Pro1824=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,613,622 control chromosomes in the GnomAD database, including 406,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 30605 hom., cov: 32)

Exomes 𝑓: 0.71 ( 376227 hom. )

Consequence

SCN8A
NM_014191.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.0570

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 12-51806958-C-A is Benign according to our data. Variant chr12-51806958-C-A is described in ClinVar as [Benign]. Clinvar id is 130251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51806958-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.057 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCN8A	NM_001330260.2 linkuse as main transcript	c.5472C>A	p.Pro1824=	synonymous_variant	27/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 linkuse as main transcript	c.5472C>A	p.Pro1824=	synonymous_variant	27/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 linkuse as main transcript	c.5349C>A	p.Pro1783=	synonymous_variant	26/26		NP_001171455.1
SCN8A	NM_001369788.1 linkuse as main transcript	c.5349C>A	p.Pro1783=	synonymous_variant	26/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.5472C>A	p.Pro1824=	synonymous_variant	27/27	1	NM_014191.4	ENSP00000346534	P4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.5472C>A	p.Pro1824=	synonymous_variant	27/27	5	NM_001330260.2	ENSP00000487583	A1	Q9UQD0-2

Frequencies

GnomAD3 genomes

AF:

0.603

AC:

91608

AN:

151874

Hom.:

30597

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.816

Gnomad AMR

AF:

0.707

Gnomad ASJ

AF:

0.657

Gnomad EAS

AF:

0.573

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.705

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.756

Gnomad OTH

AF:

0.654

GnomAD3 exomes

AF:

0.654

AC:

163303

AN:

249530

Hom.:

56723

AF XY:

0.647

AC XY:

87547

AN XY:

135340

show subpopulations

Gnomad AFR exome

AF:

0.295

Gnomad AMR exome

AF:

0.746

Gnomad ASJ exome

AF:

0.678

Gnomad EAS exome

AF:

0.574

Gnomad SAS exome

AF:

0.363

Gnomad FIN exome

AF:

0.720

Gnomad NFE exome

AF:

0.751

Gnomad OTH exome

AF:

0.686

GnomAD4 exome

AF:

0.707

AC:

1033975

AN:

1461630

Hom.:

376227

Cov.:

AF XY:

0.699

AC XY:

507872

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.291

Gnomad4 AMR exome

AF:

0.743

Gnomad4 ASJ exome

AF:

0.678

Gnomad4 EAS exome

AF:

0.529

Gnomad4 SAS exome

AF:

0.370

Gnomad4 FIN exome

AF:

0.733

Gnomad4 NFE exome

AF:

0.752

Gnomad4 OTH exome

AF:

0.685

GnomAD4 genome

AF:

0.603

AC:

91631

AN:

151992

Hom.:

30605

Cov.:

AF XY:

0.598

AC XY:

44391

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.308

Gnomad4 AMR

AF:

0.707

Gnomad4 ASJ

AF:

0.657

Gnomad4 EAS

AF:

0.572

Gnomad4 SAS

AF:

0.367

Gnomad4 FIN

AF:

0.705

Gnomad4 NFE

AF:

0.756

Gnomad4 OTH

AF:

0.649

Alfa

AF:

0.706

Hom.:

48984

Bravo

AF:

0.598

Asia WGS

AF:

0.439

AC:

1526

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -
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 88% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 82. Only high quality variants are reported. -

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 07, 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

-0.40

CADD

Benign

6.4

DANN

Benign

0.85

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