X-30665578-G-A

Variant names:

• chrX-30665578-G-A
• rs969090124
• NM_001205019.2:c.146G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_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. 15/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• inborn glycerol kinase deficiency

  Inheritance: AR, XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060578078).
• BS2: High Hemizygotes in GnomAdExome4 at 2 AR,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
GK	NM_001205019.2	c.146G>A	p.Arg49Lys	missense_variant	Exon 2 of 21	ENST00000427190.6	NP_001191948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GK	ENST00000427190.6	c.146G>A	p.Arg49Lys	missense_variant	Exon 2 of 21	5	NM_001205019.2	ENSP00000401720.2

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112400 Hom.: 0 Cov.: 23

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

African (AFR) AF: 0.00 AC: 0 AN: 23940

American (AMR) AF: 0.00 AC: 0 AN: 34998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18558

East Asian (EAS) AF: 0.00 AC: 0 AN: 29570

South Asian (SAS) AF: 0.00 AC: 0 AN: 51114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3826

European-Non Finnish (NFE) AF: 0.00000554 AC: 4 AN: 721646

Other (OTH) AF: 0.00 AC: 0 AN: 41654

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112400 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34566

African (AFR) AF: 0.00 AC: 0 AN: 30943

American (AMR) AF: 0.00 AC: 0 AN: 10559

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3612

South Asian (SAS) AF: 0.00 AC: 0 AN: 2771

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6083

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53347

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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;.
PhyloP100		1.2
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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs969090124; hg19: chrX-30683695;