chr12-51769111-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_001330260.2(SCN8A):​c.3148G>A​(p.Gly1050Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,404 control chromosomes in the GnomAD database, including 1 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. G1050A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

2
6
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 4.37

Publications

8 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 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=0.18225342).
BP6
Variant 12-51769111-G-A is Benign according to our data. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142. Variant chr12-51769111-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207142.
BS2
High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN8ANM_001330260.2 linkc.3148G>A p.Gly1050Ser missense_variant Exon 17 of 27 ENST00000627620.5 NP_001317189.1 Q9UQD0-2Q6B4S4
SCN8ANM_014191.4 linkc.3148G>A p.Gly1050Ser missense_variant Exon 17 of 27 ENST00000354534.11 NP_055006.1 Q9UQD0-1
SCN8ANM_001177984.3 linkc.3148G>A p.Gly1050Ser missense_variant Exon 17 of 26 NP_001171455.1 Q9UQD0-5
SCN8ANM_001369788.1 linkc.3148G>A p.Gly1050Ser missense_variant Exon 17 of 26 NP_001356717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN8AENST00000354534.11 linkc.3148G>A p.Gly1050Ser missense_variant Exon 17 of 27 1 NM_014191.4 ENSP00000346534.4 Q9UQD0-1
SCN8AENST00000627620.5 linkc.3148G>A p.Gly1050Ser missense_variant Exon 17 of 27 5 NM_001330260.2 ENSP00000487583.2 Q9UQD0-2
SCN8AENST00000599343.5 linkc.3181G>A p.Gly1061Ser missense_variant Exon 16 of 26 5 ENSP00000476447.3 Q9UQD0-3
SCN8AENST00000355133.7 linkc.3148G>A p.Gly1050Ser missense_variant Exon 16 of 25 1 ENSP00000347255.4 Q9UQD0-5

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.000250
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000808
AC:
20
AN:
247622
AF XY:
0.0000670
show subpopulations
Gnomad AFR exome
AF:
0.0000651
Gnomad AMR exome
AF:
0.0000874
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000561
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000125
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.000101
AC:
148
AN:
1461118
Hom.:
1
Cov.:
31
AF XY:
0.0000853
AC XY:
62
AN XY:
726786
show subpopulations
African (AFR)
AF:
0.000120
AC:
4
AN:
33470
American (AMR)
AF:
0.000157
AC:
7
AN:
44614
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39668
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86126
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53380
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.000120
AC:
133
AN:
1111624
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60356
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
10
20
31
41
51
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.000171
AC:
26
AN:
152286
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74462
show subpopulations
African (AFR)
AF:
0.000120
AC:
5
AN:
41554
American (AMR)
AF:
0.000261
AC:
4
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000250
AC:
17
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000128
Hom.:
0
Bravo
AF:
0.000155
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000234
AC:
2
ExAC
AF:
0.0000825
AC:
10
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Jan 21, 2019
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27875746, 25666757) -

May 12, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SCN8A: PP2 -

Seizures, benign familial infantile, 5 Uncertain:1
Mar 05, 2021
New York Genome Center
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The inherited heterozygous c.3148G>A (p.Gly1050Ser) variant identified in the SCN8A gene has been reported in the literature as de novo in a patient affected with hemiplegic cerebral palsy and intellectual disability [2]. The variant has been reported in ClinVar database with conflicting interpretations of pathogenicity [benign (1), likely benign (1), uncertain significance (2). Variation ID:207142]. The variant has 0.0001709 allele frequency in the gnomAD(v3) database (26 out of 152168 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The affected residue is evolutionarily conserved and is predicted deleterious by in silico predictiontools [CADD score= 22.5, REVEL score = 0.828]. Based on the available evidence, the inherited heterozygous c.3148G>A (p.Gly1050Ser) variant identified in the SCN8A gene is reported as a variant of uncertainsignificance. -

Inborn genetic diseases Benign:1
Oct 12, 2017
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy Benign:1
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

SCN8A-related disorder Benign:1
Jan 04, 2022
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.047
T
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
27
DANN
Benign
0.96
DEOGEN2
Benign
0.25
T;.;.;.;.
Eigen
Benign
0.0041
Eigen_PC
Benign
0.13
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D;.;D;D
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.18
T;T;T;T;T
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
1.4
L;L;L;.;L
PhyloP100
4.4
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.13
N;N;N;.;.
REVEL
Pathogenic
0.83
Sift
Benign
0.70
T;T;T;.;.
Sift4G
Benign
0.83
T;T;T;T;T
Polyphen
0.64
P;.;.;.;.
Vest4
0.42
MVP
0.87
MPC
1.6
ClinPred
0.044
T
GERP RS
4.5
Varity_R
0.073
gMVP
0.72
Mutation Taster
=9/91
disease causing

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

Other links and lift over

dbSNP: rs202006479; hg19: chr12-52162895; COSMIC: COSV107410022; COSMIC: COSV107410022; API