rs760459642

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_ModerateBP6_ModerateBS2

The NM_001330260.2(SCN8A):c.1601A>G(p.Asn534Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000698 in 1,432,488 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 Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.40

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 -7 ACMG points.

PP2

Missense variant in the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.436 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonus, familial, 2, developmental and epileptic encephalopathy, 13, undetermined early-onset epileptic encephalopathy, benign familial infantile epilepsy, complex neurodevelopmental disorder, seizures, benign familial infantile, 5, cognitive impairment with or without cerebellar ataxia, infantile convulsions and choreoathetosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.23127636).

BP6

Variant 12-51706681-A-G is Benign according to our data. Variant chr12-51706681-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 530522.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCN8A	NM_001330260.2 link	c.1601A>G	p.Asn534Ser	missense_variant	Exon 11 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 link	c.1601A>G	p.Asn534Ser	missense_variant	Exon 11 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 link	c.1601A>G	p.Asn534Ser	missense_variant	Exon 11 of 26		NP_001171455.1
SCN8A	NM_001369788.1 link	c.1601A>G	p.Asn534Ser	missense_variant	Exon 11 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN8A	ENST00000354534.11 link	c.1601A>G	p.Asn534Ser	missense_variant	Exon 11 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5 link	c.1601A>G	p.Asn534Ser	missense_variant	Exon 11 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5 link	c.1601A>G	p.Asn534Ser	missense_variant	Exon 10 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7 link	c.1601A>G	p.Asn534Ser	missense_variant	Exon 10 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000447

AC:

AN:

223952

AF XY:

0.00000824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000964

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000698

AC:

AN:

1432488

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

710134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32076

American (AMR)

AF:

0.00

AC:

AN:

39378

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24732

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79900

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00000727

AC:

AN:

1099758

Other (OTH)

AF:

0.00

AC:

AN:

59172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

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

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.53

.;D;.;.;.;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.017

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

D;D;D;.;D;D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.23

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.6

.;L;L;L;L;L;.

PhyloP100

4.4

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.4

.;N;N;N;.;.;.

REVEL

Uncertain

0.35

Sift

Benign

0.16

.;T;T;T;.;.;.

Sift4G

Benign

0.43

.;T;T;T;T;T;T

Polyphen

0.0080, 0.0030

.;B;.;.;B;.;.

Vest4

0.19, 0.18, 0.17, 0.17, 0.17

MutPred

0.29

Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);.;

MVP

0.88

MPC

0.79

ClinPred

0.30

GERP RS

4.4

Varity_R

0.11

gMVP

0.45

Mutation Taster

=54/46

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over