Genetic Variant SCN8A:c.928+9C>T (chr12-51699800-C-T) – ACMG Classification: Benign (-18 pts)

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.928+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 1,600,740 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

SCN8A
NM_001330260.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.432

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 12-51699800-C-T is Benign according to our data. Variant chr12-51699800-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00367 (558/152208) while in subpopulation AFR AF = 0.0127 (528/41504). AF 95% confidence interval is 0.0118. There are 2 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 558 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330260.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SCN8A	NM_001330260.2	MANE Select	c.928+9C>T	intron	N/A	NP_001317189.1
SCN8A	NM_014191.4	MANE Plus Clinical	c.928+9C>T	intron	N/A	NP_055006.1
SCN8A	NM_001177984.3		c.928+9C>T	intron	N/A	NP_001171455.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.928+9C>T	intron	N/A	ENSP00000346534.4
SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.928+9C>T	intron	N/A	ENSP00000487583.2
SCN8A	ENST00000599343.5	TSL:5	c.928+9C>T	intron	N/A	ENSP00000476447.3

Frequencies

GnomAD3 genomes

AF:

0.00368

AC:

560

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.000916

AC:

216

AN:

235824

AF XY:

0.000690

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.000606

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000189

Gnomad OTH exome

AF:

0.000864

GnomAD4 exome

AF:

0.000373

AC:

541

AN:

1448532

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

210

AN XY:

720530

show subpopulations

African (AFR)

AF:

0.0131

AC:

434

AN:

33228

American (AMR)

AF:

0.000847

AC:

AN:

43660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.0000236

AC:

AN:

84778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000907

AC:

AN:

1102562

Other (OTH)

AF:

0.000967

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00367

AC:

558

AN:

152208

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

274

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0127

AC:

528

AN:

41504

American (AMR)

AF:

0.00118

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68008

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

103

129

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:

0.00260

Hom.:

Bravo

AF:

0.00447

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Developmental and epileptic encephalopathy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.43

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over