12-51663087-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001330260.2(SCN8A):c.270G>T(p.Thr90Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T90T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.207

Publications

0 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 12-51663087-G-T is Benign according to our data. Variant chr12-51663087-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195293.

BP7

Synonymous conserved (PhyloP=0.207 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000046 (7/152334) while in subpopulation EAS AF = 0.000963 (5/5192). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCN8A	NM_001330260.2 link	c.270G>T	p.Thr90Thr	synonymous_variant	Exon 2 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 link	c.270G>T	p.Thr90Thr	synonymous_variant	Exon 2 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 link	c.270G>T	p.Thr90Thr	synonymous_variant	Exon 2 of 26		NP_001171455.1
SCN8A	NM_001369788.1 link	c.270G>T	p.Thr90Thr	synonymous_variant	Exon 2 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN8A	ENST00000354534.11 link	c.270G>T	p.Thr90Thr	synonymous_variant	Exon 2 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5 link	c.270G>T	p.Thr90Thr	synonymous_variant	Exon 2 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5 link	c.270G>T	p.Thr90Thr	synonymous_variant	Exon 1 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7 link	c.270G>T	p.Thr90Thr	synonymous_variant	Exon 1 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000961

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000105

AC:

AN:

248170

AF XY:

0.0000965

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00128

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460982

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.000580

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111244

Other (OTH)

AF:

0.000199

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000963

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 04, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Developmental and epileptic encephalopathy

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.54

CADD

Benign

9.9

(source)

DANN

Benign

0.80

PhyloP100

0.21

PromoterAI

-0.064

Neutral

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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