rs2067690303

Variant names:

• chrX-41696429-C-T
• rs2067690303
• NM_001097579.2:c.796C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• FG syndrome 4

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001097579.2. 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
	GPR34	NM_001097579.2	MANE Select	c.796C>T	p.Arg266Cys	missense	Exon 3 of 3	NP_001091048.1	Q9UPC5
	CASK	NM_001367721.1	MANE Select	c.430-24899G>A		intron	N/A	NP_001354650.1	O14936-1
	GPR34	NM_005300.4		c.796C>T	p.Arg266Cys	missense	Exon 3 of 3	NP_005291.1	Q5VT14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR34	ENST00000378142.9	TSL:1 MANE Select	c.796C>T	p.Arg266Cys	missense	Exon 3 of 3	ENSP00000367384.4	Q9UPC5
	GPR34	ENST00000378138.5	TSL:1	c.796C>T	p.Arg266Cys	missense	Exon 3 of 3	ENSP00000367378.5	Q9UPC5
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.430-24899G>A		intron	N/A	ENSP00000367405.1	O14936-1

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

African (AFR) AF: 0.00 AC: 0 AN: 25768

American (AMR) AF: 0.00 AC: 0 AN: 33391

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18736

East Asian (EAS) AF: 0.00 AC: 0 AN: 29997

South Asian (SAS) AF: 0.00 AC: 0 AN: 51823

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40005

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4049

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 828473

Other (OTH) AF: 0.0000221 AC: 1 AN: 45249

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.69		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
Mutation Taster		=84/16	polymorphism

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