X-30668024-G-A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chrX-30668024-G-A is described in Lovd as [Benign]. Variant chrX-30668024-G-A is described in Lovd as [Likely_benign].
• 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 AF XY: 0.0507 AC XY: 1753 AN XY: 34552

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

GnomAD3 exomes AF: 0.0518 AC: 9457 AN: 182677 Hom.: 208 AF XY: 0.0523 AC XY: 3521 AN XY: 67331

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 SAS exome AF: 0.0232

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

Gnomad4 AFR exome AF: 0.00829

Gnomad4 AMR exome AF: 0.0370

Gnomad4 ASJ exome AF: 0.0766

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0219

Gnomad4 FIN exome AF: 0.0640

Gnomad4 NFE exome AF: 0.0735

Gnomad4 OTH exome AF: 0.0612

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

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.0640

Gnomad4 ASJ AF: 0.0823

Gnomad4 EAS AF: 0.000275

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.0589

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.0698

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs34795481; hg19: chrX-30686141;