X-30668097-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_001205019.2(GK):ā€‹c.238A>Gā€‹(p.Ile80Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,031,362 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000035 ( 0 hom., 2 hem., cov: 23)
Exomes š‘“: 0.000019 ( 0 hom. 1 hem. )

Consequence

GK
NM_001205019.2 missense

Scores

4
13

Clinical Significance

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

Conservation

PhyloP100: 5.85
Variant links:
Genes affected
GK (HGNC:4289): (glycerol kinase) The protein encoded by this gene belongs to the FGGY kinase family. This protein is a key enzyme in the regulation of glycerol uptake and metabolism. It catalyzes the phosphorylation of glycerol by ATP, yielding ADP and glycerol-3-phosphate. Mutations in this gene are associated with glycerol kinase deficiency (GKD). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.025466949).
BP6
Variant X-30668097-A-G is Benign according to our data. Variant chrX-30668097-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2370998.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GKNM_001205019.2 linkc.238A>G p.Ile80Val missense_variant Exon 3 of 21 ENST00000427190.6 NP_001191948.1 P32189-3B4DH54

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GKENST00000427190.6 linkc.238A>G p.Ile80Val missense_variant Exon 3 of 21 5 NM_001205019.2 ENSP00000401720.2 P32189-3

Frequencies

GnomAD3 genomes
AF:
0.0000355
AC:
4
AN:
112633
Hom.:
0
Cov.:
23
AF XY:
0.0000575
AC XY:
2
AN XY:
34755
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00110
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
GnomAD3 exomes
AF:
0.0000930
AC:
17
AN:
182744
Hom.:
0
AF XY:
0.0000593
AC XY:
4
AN XY:
67426
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00116
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000222
GnomAD4 exome
AF:
0.0000185
AC:
17
AN:
918676
Hom.:
0
Cov.:
19
AF XY:
0.00000385
AC XY:
1
AN XY:
259912
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000442
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000996
GnomAD4 genome
AF:
0.0000355
AC:
4
AN:
112686
Hom.:
0
Cov.:
23
AF XY:
0.0000574
AC XY:
2
AN XY:
34818
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00110
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000102
ExAC
AF:
0.000124
AC:
15

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

GK-related disorder Uncertain:1
Aug 30, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The GK c.238A>G variant is predicted to result in the amino acid substitution p.Ile80Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-30686214-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Benign:1
May 27, 2022
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.55
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.15
.;.;T;.;.
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.87
D;D;D;D;D
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.025
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.94
L;L;L;L;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.27
N;N;.;N;N
REVEL
Benign
0.078
Sift
Benign
0.25
T;T;.;T;T
Sift4G
Benign
0.52
T;T;T;T;T
Polyphen
0.0010
.;B;.;B;.
Vest4
0.24
MutPred
0.57
Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP
0.44
MPC
0.92
ClinPred
0.093
T
GERP RS
5.6
Varity_R
0.21
gMVP
0.61

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772942427; hg19: chrX-30686214; API