Variant X-30665578-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_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

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]

GK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GK. . Gene score misZ 3.1858 (greater than the threshold 3.09). GenCC has associacion of gene with inborn glycerol kinase deficiency.

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/exons	MANE	UniProt
GK	NM_001205019.2 linkuse as main transcript	c.146G>A	p.Arg49Lys	missense_variant	2/21	ENST00000427190.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GK	ENST00000427190.6 linkuse as main transcript	c.146G>A	p.Arg49Lys	missense_variant	2/21	5	NM_001205019.2	P1	P32189-3

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

AN:

965718

Hom.:

Cov.:

AF XY:

0.00000731

AC XY:

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:

AN:

112400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2023

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

7.0

DANN

Benign

0.66

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.78

T;T;T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.061

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.96

N;N;N;N;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.40

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over