Genetic Variant SCN8A:p.Arg1932Pro (chr12-51807281-G-C) – 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.5795G>C(p.Arg1932Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R1932Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.54

Publications

3 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=0.037374765).

BP6

Variant 12-51807281-G-C is Benign according to our data. Variant chr12-51807281-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207134.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000164 (25/152074) while in subpopulation AMR AF = 0.00105 (16/15278). AF 95% confidence interval is 0.000657. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 25 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.5795G>C	p.Arg1932Pro	missense	Exon 27 of 27	NP_001317189.1	Q9UQD0-2
SCN8A	NM_014191.4	MANE Plus Clinical	c.5795G>C	p.Arg1932Pro	missense	Exon 27 of 27	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3		c.5672G>C	p.Arg1891Pro	missense	Exon 26 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.5795G>C	p.Arg1932Pro	missense	Exon 27 of 27	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.5795G>C	p.Arg1932Pro	missense	Exon 27 of 27	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5	TSL:5	c.5828G>C	p.Arg1943Pro	missense	Exon 26 of 26	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000522

AC:

AN:

249066

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000675

AC:

AN:

1111866

Other (OTH)

AF:

0.0000497

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000164

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41408

American (AMR)

AF:

0.00105

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.0000847

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Developmental and epileptic encephalopathy (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.24

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

M_CAP

Benign

0.033

MetaRNN

Benign

0.037

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

-0.44

PhyloP100

1.5

PrimateAI

Benign

0.34

PROVEAN

Benign

0.92

REVEL

Benign

0.25

Sift

Benign

1.0

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.17

MVP

0.36

MPC

1.5

ClinPred

0.043

GERP RS

4.2

Varity_R

0.099

gMVP

0.59

Mutation Taster

=60/40

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over