14-91234168-G-A

Position:

• chr14-91234168-G-A

Variant summary

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

The NM_001177676.2(GPR68):​c.883C>T​(p.Arg295Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,391,516 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: GPR68 NM_001177676.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.269

Genes affected

GPR68 (HGNC:4519): (G protein-coupled receptor 68) The protein encoded by this gene is a G protein-coupled receptor for sphingosylphosphorylcholine. The encoded protein is a proton-sensing receptor, inactive at pH 7.8 but active at pH 6.8. Mutations in this gene are a cause of amelogenesis imperfecta. [provided by RefSeq, Feb 2017]

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
GPR68	NM_001177676.2	c.883C>T	p.Arg295Trp	missense_variant	2/2	ENST00000650645.1	NP_001171147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR68	ENST00000650645.1	c.883C>T	p.Arg295Trp	missense_variant	2/2		NM_001177676.2	ENSP00000498702.1
GPR68	ENST00000531499.2	c.883C>T	p.Arg295Trp	missense_variant	2/2	1		ENSP00000434045.2
GPR68	ENST00000535815.5	c.883C>T	p.Arg295Trp	missense_variant	2/2	1		ENSP00000440797.1
GPR68	ENST00000529102.1	c.883C>T	p.Arg295Trp	missense_variant	2/2	1		ENSP00000432740.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000431 AC: 6 AN: 1391516 Hom.: 0 Cov.: 33 AF XY: 0.00000582 AC XY: 4 AN XY: 686982

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: 0.00000556

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 13, 2024

The c.883C>T (p.R295W) alteration is located in exon 2 (coding exon 1) of the GPR68 gene. This alteration results from a C to T substitution at nucleotide position 883, causing the arginine (R) at amino acid position 295 to be replaced by a tryptophan (W). 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	Benign	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.90	L;L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.21
Sift	Benign	0.077	T;T;T
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.38
MutPred		0.45		Gain of catalytic residue at T293 (P = 0);Gain of catalytic residue at T293 (P = 0);Gain of catalytic residue at T293 (P = 0);
MVP		0.37
MPC		1.8
ClinPred		0.98	D
GERP RS		-1.8
Varity_R		0.13

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: rs1027806603; hg19: chr14-91700512;