dbSNP rs2147144601: GK:p.Glu66Ala (chrX-30668056-A-C) – ACMG Classification: Uncertain_significance (2 pts)

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.87

Publications

0 publications found

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 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

GK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GK	NM_001205019.2 link	c.197A>C	p.Glu66Ala	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
GK	ENST00000427190.6 link	c.197A>C	p.Glu66Ala	missense_variant	Exon 3 of 21	5	NM_001205019.2	ENSP00000401720.2		P32189-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.76e-7

AC:

AN:

1024505

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

311063

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25032

American (AMR)

AF:

0.00

AC:

AN:

35135

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18906

East Asian (EAS)

AF:

0.00

AC:

AN:

29914

South Asian (SAS)

AF:

0.00

AC:

AN:

52661

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40497

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3615

European-Non Finnish (NFE)

AF:

0.00000129

AC:

AN:

775130

Other (OTH)

AF:

0.00

AC:

AN:

43615

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn glycerol kinase deficiency

Uncertain:1

Aug 06, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

.;.;T;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.55

D;D;D;D;D

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

L;L;L;L;.

PhyloP100

8.9

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

D;D;.;D;D

REVEL

Uncertain

0.36

Sift

Benign

0.14

T;T;.;T;T

Sift4G

Benign

0.38

T;T;T;T;T

Polyphen

0.28, 0.17

.;B;.;B;.

Vest4

0.55

MutPred

0.49

Loss of ubiquitination at K70 (P = 0.198);Loss of ubiquitination at K70 (P = 0.198);Loss of ubiquitination at K70 (P = 0.198);Loss of ubiquitination at K70 (P = 0.198);Loss of ubiquitination at K70 (P = 0.198);

MVP

0.58

MPC

1.2

ClinPred

0.90

GERP RS

5.6

Varity_R

0.73

gMVP

0.79

Mutation Taster

=42/58

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over