X-30668045-T-C

Variant names:

• chrX-30668045-T-C
• rs45537438
• NM_001205019.2:c.186T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001205019.2(GK):​c.186T>C​(p.His62His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,131,463 control chromosomes in the GnomAD database, including 2 homozygotes. There are 208 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., 115 hem., cov: 23)
  • Exomes 𝑓: 0.00040 (2 hom. 93 hem.)
• Consequence: GK NM_001205019.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.26
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant X-30668045-T-C is Benign according to our data. Variant chrX-30668045-T-C is described in ClinVar as [Benign]. Clinvar id is 711787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00358 (404/112824) while in subpopulation AFR AF = 0.0126 (393/31145). AF 95% confidence interval is 0.0116. There are 0 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 115 AR,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GK	NM_001205019.2	c.186T>C	p.His62His	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.186T>C	p.His62His	synonymous_variant	Exon 3 of 21	5	NM_001205019.2	ENSP00000401720.2

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 405 AN: 112770 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000565

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: 0.0000375

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.00120 AC: 220 AN: 183069 AF XY: 0.000886

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000401 AC: 408 AN: 1018639 Hom.: 2 Cov.: 22 AF XY: 0.000301 AC XY: 93 AN XY: 308655

African (AFR) AF: 0.0142 AC: 355 AN: 24937

American (AMR) AF: 0.000598 AC: 21 AN: 35119

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18881

East Asian (EAS) AF: 0.00 AC: 0 AN: 29886

South Asian (SAS) AF: 0.00 AC: 0 AN: 52540

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

Middle Eastern (MID) AF: 0.000286 AC: 1 AN: 3494

European-Non Finnish (NFE) AF: 0.00000390 AC: 3 AN: 769877

Other (OTH) AF: 0.000645 AC: 28 AN: 43408

GnomAD4 genome AF: 0.00358 AC: 404 AN: 112824 Hom.: 0 Cov.: 23 AF XY: 0.00329 AC XY: 115 AN XY: 34964

African (AFR) AF: 0.0126 AC: 393 AN: 31145

American (AMR) AF: 0.000564 AC: 6 AN: 10633

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3639

South Asian (SAS) AF: 0.00 AC: 0 AN: 2751

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6203

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53361

Other (OTH) AF: 0.00195 AC: 3 AN: 1537

Alfa AF: 0.00213 Hom.: 9

Bravo AF: 0.00425

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GK-related disorder Benign:1

Apr 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.4
DANN	Benign	0.70
PhyloP100		1.3
Mutation Taster		=298/2	polymorphism (auto)

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: rs45537438; hg19: chrX-30686162;