dbSNP rs375785915: SCN8A:c.3820-7T>C (chr12-51780642-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001330260.2(SCN8A):c.3820-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 1,448,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 22)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 splice_region, intron

Scores

Splicing: ADA: 0.00006663

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.753

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 12-51780642-T-C is Benign according to our data. Variant chr12-51780642-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461341.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 = 0.000189 (28/147980) while in subpopulation AFR AF = 0.000651 (26/39924). AF 95% confidence interval is 0.000456. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 28 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.3820-7T>C	splice_region intron	N/A	NP_001317189.1
SCN8A	NM_014191.4	MANE Plus Clinical	c.3820-7T>C	splice_region intron	N/A	NP_055006.1
SCN8A	NM_001177984.3		c.3820-5900T>C	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.3820-7T>C	splice_region intron	N/A	ENSP00000346534.4
SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.3820-7T>C	splice_region intron	N/A	ENSP00000487583.2
SCN8A	ENST00000599343.5	TSL:5	c.3853-7T>C	splice_region intron	N/A	ENSP00000476447.3

Frequencies

GnomAD3 genomes

AF:

0.000189

AC:

AN:

147868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000676

AC:

AN:

133124

AF XY:

0.0000274

show subpopulations

Gnomad AFR exome

AF:

0.000654

Gnomad AMR exome

AF:

0.000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000309

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1300096

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

643314

show subpopulations

African (AFR)

AF:

0.000543

AC:

AN:

25794

American (AMR)

AF:

0.000438

AC:

AN:

18252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22010

East Asian (EAS)

AF:

0.00

AC:

AN:

31828

South Asian (SAS)

AF:

0.00

AC:

AN:

64982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47682

Middle Eastern (MID)

AF:

0.000202

AC:

AN:

4948

European-Non Finnish (NFE)

AF:

0.00000194

AC:

AN:

1031250

Other (OTH)

AF:

0.0000562

AC:

AN:

53350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.000189

AC:

AN:

147980

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

AN XY:

72092

show subpopulations

African (AFR)

AF:

0.000651

AC:

AN:

39924

American (AMR)

AF:

0.000136

AC:

AN:

14738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.00

AC:

AN:

4970

South Asian (SAS)

AF:

0.00

AC:

AN:

4484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67210

Other (OTH)

AF:

0.00

AC:

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

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:

0.0000932

Hom.:

Bravo

AF:

0.000280

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy (1)

not provided (1)

not specified (1)

SCN8A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.5

(source)

DANN

Benign

0.63

PhyloP100

0.75

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000067

dbscSNV1_RF

Benign

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over