Variant 14-91234531-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001177676.2(GPR68):c.520G>C(p.Glu174Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GPR68
NM_001177676.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90

Variant links:

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]

GPR68 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR68	NM_001177676.2 linkuse as main transcript	c.520G>C	p.Glu174Gln	missense_variant	2/2	ENST00000650645.1	NP_001171147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GPR68	ENST00000650645.1 linkuse as main transcript	c.520G>C	p.Glu174Gln	missense_variant	2/2		NM_001177676.2	ENSP00000498702	P1
GPR68	ENST00000531499.2 linkuse as main transcript	c.520G>C	p.Glu174Gln	missense_variant	2/2	1		ENSP00000434045	P1
GPR68	ENST00000535815.5 linkuse as main transcript	c.520G>C	p.Glu174Gln	missense_variant	2/2	1		ENSP00000440797	P1
GPR68	ENST00000529102.1 linkuse as main transcript	c.520G>C	p.Glu174Gln	missense_variant	2/2	1		ENSP00000432740

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727198

show subpopulations

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.520G>C (p.E174Q) alteration is located in exon 2 (coding exon 1) of the GPR68 gene. This alteration results from a G to C substitution at nucleotide position 520, causing the glutamic acid (E) at amino acid position 174 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

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0080

D;D;D

Sift4G

Benign

0.090

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.78

MutPred

0.64

Gain of catalytic residue at E174 (P = 2e-04);Gain of catalytic residue at E174 (P = 2e-04);Gain of catalytic residue at E174 (P = 2e-04);

MVP

0.52

MPC

1.7

ClinPred

1.0

GERP RS

5.1

Varity_R

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over