X-30668056-A-C

Variant names:

• chrX-30668056-A-C
• rs2147144601
• NM_001205019.2:c.197A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001205019.2(GK):​c.197A>C​(p.Glu66Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000976 in 1,024,505 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.8e-7 (0 hom. 0 hem.)
• Consequence: GK NM_001205019.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87
• 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: XL, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001205019.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GK	NM_001205019.2	MANE Select	c.197A>C	p.Glu66Ala	missense	Exon 3 of 21	NP_001191948.1	P32189-3
	GK	NM_001437590.1		c.197A>C	p.Glu66Ala	missense	Exon 3 of 21	NP_001424519.1	A0A8I5KXY7
	GK	NM_001128127.3		c.197A>C	p.Glu66Ala	missense	Exon 3 of 20	NP_001121599.1	P32189-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GK	ENST00000427190.6	TSL:5 MANE Select	c.197A>C	p.Glu66Ala	missense	Exon 3 of 21	ENSP00000401720.2	P32189-3
	GK	ENST00000378943.7	TSL:1	c.197A>C	p.Glu66Ala	missense	Exon 3 of 20	ENSP00000368226.3	P32189-2
	GK	ENST00000378946.7	TSL:1	c.197A>C	p.Glu66Ala	missense	Exon 3 of 20	ENSP00000368229.3	P32189-4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.76e-7 AC: 1 AN: 1024505 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 311063

African (AFR) AF: 0.00 AC: 0 AN: 25032

American (AMR) AF: 0.00 AC: 0 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18906

East Asian (EAS) AF: 0.00 AC: 0 AN: 29914

South Asian (SAS) AF: 0.00 AC: 0 AN: 52661

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40497

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3615

European-Non Finnish (NFE) AF: 0.00000129 AC: 1 AN: 775130

Other (OTH) AF: 0.00 AC: 0 AN: 43615

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn glycerol kinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L
PhyloP100		8.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.36
Sift	Benign	0.14	T
Sift4G	Benign	0.38	T
Polyphen		0.28	B
Vest4		0.55
MutPred		0.49		Loss of ubiquitination at K70 (P = 0.198)
MVP		0.58
MPC		1.2
ClinPred		0.90	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.79
Mutation Taster		=42/58	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

Other links and lift over

dbSNP: rs2147144601; hg19: chrX-30686173;