NM_001205019.2:c.165G>A

Variant names:

• chrX-30668024-G-A
• rs34795481
• NM_001205019.2:c.165G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001205019.2(GK):​c.165G>A​(p.Gln55Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,089,656 control chromosomes in the GnomAD database, including 1,886 homozygotes. There are 19,090 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (173 hom., 1753 hem., cov: 23)
  • Exomes 𝑓: 0.065 (1713 hom. 17337 hem.)
• Consequence: GK NM_001205019.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant X-30668024-G-A is Benign according to our data. Variant chrX-30668024-G-A is described in ClinVar as [Benign]. Clinvar id is 590201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GK	NM_001205019.2	c.165G>A	p.Gln55Gln	synonymous_variant	Exon 3 of 21	ENST00000427190.6	NP_001191948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GK	ENST00000427190.6	c.165G>A	p.Gln55Gln	synonymous_variant	Exon 3 of 21	5	NM_001205019.2	ENSP00000401720.2

Frequencies

GnomAD3 genomes AF: 0.0532 AC: 5982 AN: 112368 Hom.: 173 Cov.: 23

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0748

Gnomad AMR AF: 0.0640

Gnomad ASJ AF: 0.0823

Gnomad EAS AF: 0.000275

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.0589

Gnomad MID AF: 0.0628

Gnomad NFE AF: 0.0776

Gnomad OTH AF: 0.0706

GnomAD2 exomes AF: 0.0518 AC: 9457 AN: 182677 AF XY: 0.0523

Gnomad AFR exome AF: 0.00890

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0804

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.0639

Gnomad NFE exome AF: 0.0744

Gnomad OTH exome AF: 0.0626

GnomAD4 exome AF: 0.0647 AC: 63217 AN: 977235 Hom.: 1713 Cov.: 21 AF XY: 0.0593 AC XY: 17337 AN XY: 292207

African (AFR) AF: 0.00829 AC: 201 AN: 24244

American (AMR) AF: 0.0370 AC: 1298 AN: 35066

Ashkenazi Jewish (ASJ) AF: 0.0766 AC: 1426 AN: 18624

East Asian (EAS) AF: 0.000101 AC: 3 AN: 29712

South Asian (SAS) AF: 0.0219 AC: 1131 AN: 51739

European-Finnish (FIN) AF: 0.0640 AC: 2590 AN: 40462

Middle Eastern (MID) AF: 0.0628 AC: 194 AN: 3087

European-Non Finnish (NFE) AF: 0.0735 AC: 53800 AN: 732264

Other (OTH) AF: 0.0612 AC: 2574 AN: 42037

GnomAD4 genome AF: 0.0532 AC: 5980 AN: 112421 Hom.: 173 Cov.: 23 AF XY: 0.0506 AC XY: 1753 AN XY: 34615

African (AFR) AF: 0.0115 AC: 359 AN: 31087

American (AMR) AF: 0.0640 AC: 678 AN: 10589

Ashkenazi Jewish (ASJ) AF: 0.0823 AC: 218 AN: 2648

East Asian (EAS) AF: 0.000275 AC: 1 AN: 3630

South Asian (SAS) AF: 0.0251 AC: 69 AN: 2751

European-Finnish (FIN) AF: 0.0589 AC: 357 AN: 6057

Middle Eastern (MID) AF: 0.0642 AC: 14 AN: 218

European-Non Finnish (NFE) AF: 0.0775 AC: 4127 AN: 53240

Other (OTH) AF: 0.0698 AC: 106 AN: 1519

Alfa AF: 0.0685 Hom.: 741

Bravo AF: 0.0518

EpiCase AF: 0.0831

EpiControl AF: 0.0798

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Sep 07, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.7
DANN	Benign	0.52
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=290/10	polymorphism (auto)

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: rs34795481; hg19: chrX-30686141;