12-51687181-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 13
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
cognitive impairment with or without cerebellar ataxia
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
seizures, benign familial infantile, 5
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
benign familial infantile epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile convulsions and choreoathetosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myoclonus, familial, 2
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SCN8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 130253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2 link	c.576C>T	p.Asp192Asp	synonymous_variant	Exon 5 of 27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 link	c.576C>T	p.Asp192Asp	synonymous_variant	Exon 5 of 27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 link	c.576C>T	p.Asp192Asp	synonymous_variant	Exon 5 of 26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 link	c.576C>T	p.Asp192Asp	synonymous_variant	Exon 5 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 link	c.576C>T	p.Asp192Asp	synonymous_variant	Exon 5 of 27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 link	c.576C>T	p.Asp192Asp	synonymous_variant	Exon 5 of 27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 link	c.576C>T	p.Asp192Asp	synonymous_variant	Exon 4 of 26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 link	c.576C>T	p.Asp192Asp	synonymous_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.848

AC:

211106

AN:

249070

AF XY:

0.838

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 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

African (AFR)

AF:

0.645

AC:

21554

AN:

33412

American (AMR)

AF:

0.913

AC:

40791

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.810

AC:

21143

AN:

26114

East Asian (EAS)

AF:

0.995

AC:

39492

AN:

39690

South Asian (SAS)

AF:

0.679

AC:

58535

AN:

86194

European-Finnish (FIN)

AF:

0.913

AC:

48735

AN:

53398

Middle Eastern (MID)

AF:

0.772

AC:

4449

AN:

5762

European-Non Finnish (NFE)

AF:

0.869

AC:

965888

AN:

1111196

Other (OTH)

AF:

0.846

AC:

51008

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

9198

18396

27593

36791

45989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21216

42432

63648

84864

106080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.812

AC:

123455

AN:

152096

Hom.:

51038

Cov.:

AF XY:

0.813

AC XY:

60480

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.654

AC:

27076

AN:

41408

American (AMR)

AF:

0.872

AC:

13327

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.785

AC:

2723

AN:

3470

East Asian (EAS)

AF:

0.993

AC:

5149

AN:

5186

South Asian (SAS)

AF:

0.689

AC:

3315

AN:

4814

European-Finnish (FIN)

AF:

0.918

AC:

9739

AN:

10608

Middle Eastern (MID)

AF:

0.764

AC:

223

AN:

292

European-Non Finnish (NFE)

AF:

0.872

AC:

59304

AN:

68016

Other (OTH)

AF:

0.833

AC:

1758

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1108

2217

3325

4434

5542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.847

Hom.:

97880

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

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 22, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:3

May 06, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 31, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Cognitive impairment with or without cerebellar ataxia

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Seizures, benign familial infantile, 5

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myoclonus, familial, 2

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 13

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.9

(source)

DANN

Benign

0.89

PhyloP100

-0.82

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over