Genetic Variant NM_001330260.2:c.3076C>T (chr12-51769039-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001330260.2(SCN8A):c.3076C>T(p.Arg1026Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,932 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1026L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 32)

Exomes 𝑓: 0.013 ( 167 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 1.53

Publications

10 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, STRONG Submitted by: ClinGen, PanelApp Australia
developmental and epileptic encephalopathy, 13
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
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 -12 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=0.006647438).

BP6

Variant 12-51769039-C-T is Benign according to our data. Variant chr12-51769039-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130244.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0107 (1629/152276) while in subpopulation NFE AF = 0.0146 (991/68024). AF 95% confidence interval is 0.0138. There are 16 homozygotes in GnomAd4. There are 879 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1629 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	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN8A	NM_001330260.2	MANE Select	c.3076C>T	p.Arg1026Cys	missense	Exon 17 of 27	NP_001317189.1	Q9UQD0-2
SCN8A	NM_014191.4	MANE Plus Clinical	c.3076C>T	p.Arg1026Cys	missense	Exon 17 of 27	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3		c.3076C>T	p.Arg1026Cys	missense	Exon 17 of 26	NP_001171455.1	Q9UQD0-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.3076C>T	p.Arg1026Cys	missense	Exon 17 of 27	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.3076C>T	p.Arg1026Cys	missense	Exon 17 of 27	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5	TSL:5	c.3109C>T	p.Arg1037Cys	missense	Exon 16 of 26	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1630

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0351

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.0117

AC:

2916

AN:

249052

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00467

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0308

Gnomad NFE exome

AF:

0.0147

Gnomad OTH exome

AF:

0.00975

GnomAD4 exome

AF:

0.0127

AC:

18504

AN:

1461656

Hom.:

167

Cov.:

AF XY:

0.0127

AC XY:

9228

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33480

American (AMR)

AF:

0.00490

AC:

219

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

520

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00470

AC:

405

AN:

86252

European-Finnish (FIN)

AF:

0.0299

AC:

1596

AN:

53400

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0135

AC:

15057

AN:

1111834

Other (OTH)

AF:

0.0106

AC:

638

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1201

2401

3602

4802

6003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.0107

AC:

1629

AN:

152276

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

879

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41552

American (AMR)

AF:

0.00490

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0351

AC:

372

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

991

AN:

68024

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

172

259

345

431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0132

Hom.:

Bravo

AF:

0.00829

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00193

AC:

ESP6500EA

AF:

0.0155

AC:

131

ExAC

AF:

0.0117

AC:

1419

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0115

EpiControl

AF:

0.0138

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Developmental and epileptic encephalopathy (1)

Developmental and epileptic encephalopathy, 13 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0066

MetaSVM

Uncertain

0.072

MutationAssessor

Benign

1.8

PhyloP100

1.5

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.33

MPC

1.4

ClinPred

0.027

GERP RS

4.5

Varity_R

0.49

gMVP

0.75

Mutation Taster

=97/3

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

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