chr12-51770005-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001330260.2(SCN8A):c.3490+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 1,513,632 control chromosomes in the GnomAD database, including 516,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 45915 hom., cov: 32)

Exomes 𝑓: 0.83 ( 470842 hom. )

Consequence

SCN8A
NM_001330260.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.162

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-51770005-G-A is Benign according to our data. Variant chr12-51770005-G-A is described in ClinVar as [Benign]. Clinvar id is 260352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2 link	c.3490+20G>A	intron_variant	Intron 18 of 26	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 link	c.3490+20G>A	intron_variant	Intron 18 of 26	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 link	c.3490+20G>A	intron_variant	Intron 18 of 25		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 link	c.3490+20G>A	intron_variant	Intron 18 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 link	c.3490+20G>A	intron_variant	Intron 18 of 26	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 link	c.3490+20G>A	intron_variant	Intron 18 of 26	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 link	c.3523+20G>A	intron_variant	Intron 17 of 25	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 link	c.3490+20G>A	intron_variant	Intron 17 of 24	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

AF:

0.764

AC:

116093

AN:

152016

Hom.:

45904

Cov.:

show subpopulations

Gnomad AFR

AF:

0.552

Gnomad AMI

AF:

0.886

Gnomad AMR

AF:

0.853

Gnomad ASJ

AF:

0.802

Gnomad EAS

AF:

0.891

Gnomad SAS

AF:

0.576

Gnomad FIN

AF:

0.900

Gnomad MID

AF:

0.717

Gnomad NFE

AF:

0.850

Gnomad OTH

AF:

0.792

GnomAD2 exomes

AF:

0.807

AC:

147815

AN:

183064

AF XY:

0.795

show subpopulations

Gnomad AFR exome

AF:

0.559

Gnomad AMR exome

AF:

0.888

Gnomad ASJ exome

AF:

0.821

Gnomad EAS exome

AF:

0.885

Gnomad FIN exome

AF:

0.902

Gnomad NFE exome

AF:

0.847

Gnomad OTH exome

AF:

0.815

GnomAD4 exome

AF:

0.828

AC:

1126696

AN:

1361498

Hom.:

470842

Cov.:

AF XY:

0.820

AC XY:

554263

AN XY:

676000

show subpopulations

African (AFR)

AF:

0.548

AC:

17040

AN:

31108

American (AMR)

AF:

0.882

AC:

33067

AN:

37502

Ashkenazi Jewish (ASJ)

AF:

0.821

AC:

20535

AN:

25026

East Asian (EAS)

AF:

0.903

AC:

33403

AN:

36988

South Asian (SAS)

AF:

0.573

AC:

45118

AN:

78774

European-Finnish (FIN)

AF:

0.899

AC:

45670

AN:

50814

Middle Eastern (MID)

AF:

0.719

AC:

3528

AN:

4904

European-Non Finnish (NFE)

AF:

0.848

AC:

881944

AN:

1039446

Other (OTH)

AF:

0.815

AC:

46391

AN:

56936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

9528

19055

28583

38110

47638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.763

AC:

116137

AN:

152134

Hom.:

45915

Cov.:

AF XY:

0.763

AC XY:

56797

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.552

AC:

22877

AN:

41458

American (AMR)

AF:

0.854

AC:

13058

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.802

AC:

2784

AN:

3472

East Asian (EAS)

AF:

0.891

AC:

4594

AN:

5158

South Asian (SAS)

AF:

0.577

AC:

2781

AN:

4822

European-Finnish (FIN)

AF:

0.900

AC:

9552

AN:

10612

Middle Eastern (MID)

AF:

0.723

AC:

211

AN:

292

European-Non Finnish (NFE)

AF:

0.850

AC:

57809

AN:

67996

Other (OTH)

AF:

0.787

AC:

1663

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1263

2527

3790

5054

6317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.821

Hom.:

84219

Bravo

AF:

0.757

Asia WGS

AF:

0.685

AC:

2378

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

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 96% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 89. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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

- -

not provided

Benign:2

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

- -

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

-0.83

CADD

Benign

0.86

(source)

DANN

Benign

0.31

PhyloP100

-0.16

Mutation Taster

=100/0

polymorphism (auto)

(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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chr12-51770005-G-A

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