12-51790487-T-C

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.4509T>C(p.Pro1503Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,605,698 control chromosomes in the GnomAD database, including 409,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 31602 hom., cov: 32)

Exomes 𝑓: 0.71 ( 377731 hom. )

Consequence

SCN8A
NM_001330260.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.204

Publications

29 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=-0.53).

BP6

Variant 12-51790487-T-C is Benign according to our data. Variant chr12-51790487-T-C is described in ClinVar as Benign. ClinVar VariationId is 130247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.204 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCN8A	NM_001330260.2 link	c.4509T>C	p.Pro1503Pro	synonymous_variant	Exon 25 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 link	c.4509T>C	p.Pro1503Pro	synonymous_variant	Exon 25 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 link	c.4386T>C	p.Pro1462Pro	synonymous_variant	Exon 24 of 26		NP_001171455.1
SCN8A	NM_001369788.1 link	c.4386T>C	p.Pro1462Pro	synonymous_variant	Exon 24 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN8A	ENST00000354534.11 link	c.4509T>C	p.Pro1503Pro	synonymous_variant	Exon 25 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5 link	c.4509T>C	p.Pro1503Pro	synonymous_variant	Exon 25 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5 link	c.4542T>C	p.Pro1514Pro	synonymous_variant	Exon 24 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7 link	c.4386T>C	p.Pro1462Pro	synonymous_variant	Exon 23 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes

AF:

0.619

AC:

93999

AN:

151974

Hom.:

31592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.351

Gnomad AMI

AF:

0.815

Gnomad AMR

AF:

0.725

Gnomad ASJ

AF:

0.657

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.363

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.758

Gnomad OTH

AF:

0.666

GnomAD2 exomes

AF:

0.659

AC:

160565

AN:

243610

AF XY:

0.650

show subpopulations

Gnomad AFR exome

AF:

0.340

Gnomad AMR exome

AF:

0.753

Gnomad ASJ exome

AF:

0.678

Gnomad EAS exome

AF:

0.575

Gnomad FIN exome

AF:

0.725

Gnomad NFE exome

AF:

0.752

Gnomad OTH exome

AF:

0.686

GnomAD4 exome

AF:

0.711

AC:

1033818

AN:

1453606

Hom.:

377731

Cov.:

AF XY:

0.702

AC XY:

507484

AN XY:

722938

show subpopulations

African (AFR)

AF:

0.336

AC:

11129

AN:

33156

American (AMR)

AF:

0.751

AC:

32971

AN:

43932

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

17658

AN:

26032

East Asian (EAS)

AF:

0.532

AC:

20866

AN:

39228

South Asian (SAS)

AF:

0.367

AC:

31161

AN:

84852

European-Finnish (FIN)

AF:

0.737

AC:

39321

AN:

53334

Middle Eastern (MID)

AF:

0.620

AC:

3563

AN:

5744

European-Non Finnish (NFE)

AF:

0.755

AC:

835694

AN:

1107254

Other (OTH)

AF:

0.690

AC:

41455

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

12195

24390

36586

48781

60976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19942

39884

59826

79768

99710

<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:

0.618

AC:

94028

AN:

152092

Hom.:

31602

Cov.:

AF XY:

0.613

AC XY:

45614

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.351

AC:

14549

AN:

41472

American (AMR)

AF:

0.726

AC:

11102

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.657

AC:

2281

AN:

3470

East Asian (EAS)

AF:

0.577

AC:

2988

AN:

5176

South Asian (SAS)

AF:

0.365

AC:

1757

AN:

4814

European-Finnish (FIN)

AF:

0.710

AC:

7503

AN:

10574

Middle Eastern (MID)

AF:

0.609

AC:

179

AN:

294

European-Non Finnish (NFE)

AF:

0.758

AC:

51529

AN:

67970

Other (OTH)

AF:

0.661

AC:

1397

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1597

3193

4790

6386

7983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.702

Hom.:

138157

Bravo

AF:

0.615

Asia WGS

AF:

0.446

AC:

1548

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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 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. -

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

- -

not provided

Benign:3

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

- -

May 07, 2018

Athena Diagnostics

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. -

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

- -

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

- -

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

-0.53

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

-0.20

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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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