X-30665578-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001205019.2(GK):​c.146G>A​(p.Arg49Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000464 in 1,078,118 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0000041 ( 0 hom. 2 hem. )

Consequence

GK
NM_001205019.2 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.060578078).
BS2
High Hemizygotes in GnomAdExome4 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.146G>A p.Arg49Lys missense_variant Exon 2 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.146G>A p.Arg49Lys missense_variant Exon 2 of 21 5 NM_001205019.2 ENSP00000401720.2 P32189-3

Frequencies

GnomAD3 genomes
AF:
0.00000890
AC:
1
AN:
112400
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34566
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000187
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000414
AC:
4
AN:
965718
Hom.:
0
Cov.:
19
AF XY:
0.00000731
AC XY:
2
AN XY:
273604
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000554
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000890
AC:
1
AN:
112400
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34566
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000187
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 29, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.146G>A (p.R49K) alteration is located in exon 2 (coding exon 2) of the GK gene. This alteration results from a G to A substitution at nucleotide position 146, causing the arginine (R) at amino acid position 49 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.87
CADD
Benign
7.0
DANN
Benign
0.66
DEOGEN2
Benign
0.15
.;.;T;.;.
FATHMM_MKL
Benign
0.51
D
LIST_S2
Benign
0.78
T;T;T;T;T
M_CAP
Benign
0.0040
T
MetaRNN
Benign
0.061
T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-0.96
N;N;N;N;.
PrimateAI
Benign
0.40
T
PROVEAN
Benign
0.56
N;N;.;N;N
REVEL
Benign
0.048
Sift
Benign
1.0
T;T;.;T;T
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.0
.;B;.;B;.
Vest4
0.097
MutPred
0.44
Gain of methylation at R49 (P = 0.0082);Gain of methylation at R49 (P = 0.0082);Gain of methylation at R49 (P = 0.0082);Gain of methylation at R49 (P = 0.0082);Gain of methylation at R49 (P = 0.0082);
MVP
0.39
MPC
1.1
ClinPred
0.055
T
GERP RS
0.66
Varity_R
0.10
gMVP
0.40

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: rs969090124; hg19: chrX-30683695; API