chrX-41696429-C-T

Position:

• chrX-41696429-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001097579.2(GPR34):​c.796C>T​(p.Arg266Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,077,491 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: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: GPR34 NM_001097579.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

Genes affected

GPR34 (HGNC:4490): (G protein-coupled receptor 34) G protein-coupled receptors (GPCRs), such as GPR34, are integral membrane proteins containing 7 putative transmembrane domains (TMs). These proteins mediate signals to the interior of the cell via activation of heterotrimeric G proteins that in turn activate various effector proteins, ultimately resulting in a physiologic response.[supplied by OMIM, Apr 2006]

CASK (HGNC:1497): (calcium/calmodulin dependent serine protein kinase) This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and a form of X-linked intellectual disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

CASK (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR34	NM_001097579.2	c.796C>T	p.Arg266Cys	missense_variant	3/3	ENST00000378142.9	NP_001091048.1
CASK	NM_001367721.1	c.430-24899G>A		intron_variant		ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR34	ENST00000378142.9	c.796C>T	p.Arg266Cys	missense_variant	3/3	1	NM_001097579.2	ENSP00000367384.4
CASK	ENST00000378163.7	c.430-24899G>A		intron_variant		5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1077491 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 346491

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000121

Gnomad4 OTH exome AF: 0.0000221

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2023

The c.796C>T (p.R266C) alteration is located in exon 3 (coding exon 1) of the GPR34 gene. This alteration results from a C to T substitution at nucleotide position 796, causing the arginine (R) at amino acid position 266 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.;T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	2.9	M;M;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.1	D;D;.;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;.
Polyphen		1.0	D;D;.;D
Vest4		0.51
MutPred		0.69		Loss of methylation at R266 (P = 0.0289);Loss of methylation at R266 (P = 0.0289);.;Loss of methylation at R266 (P = 0.0289);
MVP		0.89
MPC		2.0
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.37
gMVP		0.85

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: rs2067690303; hg19: chrX-41555682; COSMIC: COSV59368142; COSMIC: COSV59368142;