14-91234544-G-C

Position:

• chr14-91234544-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001177676.2(GPR68):​c.507C>G​(p.His169Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPR68 NM_001177676.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.924

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 3 ACMG points.

• PM1: In a mutagenesis_site Failed to stimulate IP formation at pH 6.8, activity is restored at more acid pH. (size 0) in uniprot entity OGR1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4021648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR68	NM_001177676.2	c.507C>G	p.His169Gln	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.507C>G	p.His169Gln	missense_variant	2/2		NM_001177676.2	ENSP00000498702	P1
GPR68	ENST00000531499.2	c.507C>G	p.His169Gln	missense_variant	2/2	1		ENSP00000434045	P1
GPR68	ENST00000535815.5	c.507C>G	p.His169Gln	missense_variant	2/2	1		ENSP00000440797	P1
GPR68	ENST00000529102.1	c.507C>G	p.His169Gln	missense_variant	2/2	1		ENSP00000432740

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Apr 12, 2023

The c.507C>G (p.H169Q) alteration is located in exon 2 (coding exon 1) of the GPR68 gene. This alteration results from a C to G substitution at nucleotide position 507, causing the histidine (H) at amino acid position 169 to be replaced by a glutamine (Q). 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	0.29
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;L;.
MutationTaster	Benign	0.88	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.099
Sift	Benign	0.056	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.93	P;P;.
Vest4		0.24
MutPred		0.50		Gain of catalytic residue at E174 (P = 9e-04);Gain of catalytic residue at E174 (P = 9e-04);Gain of catalytic residue at E174 (P = 9e-04);
MVP		0.53
MPC		1.1
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-91700888;