NM_001205019.2:c.259+2T>C

Variant names:

• chrX-30668120-T-C
• rs1057520781
• NM_001205019.2:c.259+2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001205019.2(GK):​c.259+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GK NM_001205019.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9867
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.61
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.063690476 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of -45, new splice context is: catGTgaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-30668120-T-C is Pathogenic according to our data. Variant chrX-30668120-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 379913.Status of the report is criteria_provided_single_submitter, 1 stars.

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.259+2T>C		splice_donor intron	N/A	NP_001191948.1	P32189-3
	GK	NM_001437590.1		c.259+2T>C		splice_donor intron	N/A	NP_001424519.1	A0A8I5KXY7
	GK	NM_001128127.3		c.259+2T>C		splice_donor intron	N/A	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.259+2T>C		splice_donor intron	N/A	ENSP00000401720.2	P32189-3
	GK	ENST00000378943.7	TSL:1	c.259+2T>C		splice_donor intron	N/A	ENSP00000368226.3	P32189-2
	GK	ENST00000378946.7	TSL:1	c.259+2T>C		splice_donor intron	N/A	ENSP00000368229.3	P32189-4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 803746 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 222024

African (AFR) AF: 0.00 AC: 0 AN: 21011

American (AMR) AF: 0.00 AC: 0 AN: 34802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17526

East Asian (EAS) AF: 0.00 AC: 0 AN: 28886

South Asian (SAS) AF: 0.00 AC: 0 AN: 48147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40393

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3545

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 573042

Other (OTH) AF: 0.00 AC: 0 AN: 36394

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.6
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057520781; hg19: chrX-30686237;