rs187327463

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001330260.2(SCN8A):c.3822C>T(p.Val1274Val) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00205 in 1,254,198 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 23)

Exomes 𝑓: 0.0021 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 5.05

Publications

1 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 12-51780651-C-T is Benign according to our data. Variant chr12-51780651-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00136 (168/123406) while in subpopulation NFE AF = 0.00191 (116/60846). AF 95% confidence interval is 0.00162. There are 2 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCN8A	NM_001330260.2 link	c.3822C>T	p.Val1274Val	splice_region_variant, synonymous_variant	Exon 21 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 link	c.3822C>T	p.Val1274Val	splice_region_variant, synonymous_variant	Exon 21 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 link	c.3820-5891C>T		intron_variant	Intron 20 of 25		NP_001171455.1
SCN8A	NM_001369788.1 link	c.3820-5891C>T		intron_variant	Intron 20 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN8A	ENST00000354534.11 link	c.3822C>T	p.Val1274Val	splice_region_variant, synonymous_variant	Exon 21 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5 link	c.3822C>T	p.Val1274Val	splice_region_variant, synonymous_variant	Exon 21 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5 link	c.3855C>T	p.Val1285Val	splice_region_variant, synonymous_variant	Exon 20 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7 link	c.3820-5891C>T		intron_variant	Intron 19 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

168

AN:

123330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000184

Gnomad AMI

AF:

0.00124

Gnomad AMR

AF:

0.000660

Gnomad ASJ

AF:

0.00856

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000590

Gnomad FIN

AF:

0.00111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00121

GnomAD2 exomes

AF:

0.00180

AC:

251

AN:

139640

AF XY:

0.00186

show subpopulations

Gnomad AFR exome

AF:

0.000406

Gnomad AMR exome

AF:

0.000577

Gnomad ASJ exome

AF:

0.00681

Gnomad EAS exome

AF:

0.000648

Gnomad FIN exome

AF:

0.000766

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.00193

GnomAD4 exome

AF:

0.00212

AC:

2402

AN:

1130792

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

1174

AN XY:

556316

show subpopulations

African (AFR)

AF:

0.000319

AC:

AN:

21966

American (AMR)

AF:

0.00132

AC:

AN:

18204

Ashkenazi Jewish (ASJ)

AF:

0.0105

AC:

166

AN:

15742

East Asian (EAS)

AF:

0.00

AC:

AN:

16662

South Asian (SAS)

AF:

0.00111

AC:

AN:

59478

European-Finnish (FIN)

AF:

0.000808

AC:

AN:

33426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4180

European-Non Finnish (NFE)

AF:

0.00218

AC:

2003

AN:

919310

Other (OTH)

AF:

0.00261

AC:

109

AN:

41824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

164

246

328

410

<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:

0.00136

AC:

168

AN:

123406

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

58116

show subpopulations

African (AFR)

AF:

0.000184

AC:

AN:

32672

American (AMR)

AF:

0.000659

AC:

AN:

10628

Ashkenazi Jewish (ASJ)

AF:

0.00856

AC:

AN:

3156

East Asian (EAS)

AF:

0.00

AC:

AN:

3708

South Asian (SAS)

AF:

0.000589

AC:

AN:

3396

European-Finnish (FIN)

AF:

0.00111

AC:

AN:

6316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.00191

AC:

116

AN:

60846

Other (OTH)

AF:

0.00120

AC:

AN:

1664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00178

Hom.:

Bravo

AF:

0.00134

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 27, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN8A: BP4, BS1 -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Feb 10, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 16, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 12, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Developmental and epileptic encephalopathy

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 13

Benign:1

May 28, 2019

Mendelics

Significance:Likely 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

-0.30

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

5.0

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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