rs1057517671

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_001177676.2(GPR68):c.667_668delAA(p.Lys223GlyfsTer113) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,932 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GPR68
NM_001177676.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 8.01

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

amelogenesis imperfecta, hypomaturation type, IIa6
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
amelogenesis imperfecta type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GPR68 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.393 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-91234382-CTT-C is Pathogenic according to our data. Variant chr14-91234382-CTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 268085.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177676.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPR68	NM_001177676.2	MANE Select	c.667_668delAA	p.Lys223GlyfsTer113	frameshift	Exon 2 of 2	NP_001171147.1
GPR68	NM_001348437.1		c.667_668delAA	p.Lys223GlyfsTer113	frameshift	Exon 3 of 3	NP_001335366.1
GPR68	NM_003485.3		c.667_668delAA	p.Lys223GlyfsTer113	frameshift	Exon 2 of 2	NP_003476.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPR68	ENST00000650645.1	MANE Select	c.667_668delAA	p.Lys223GlyfsTer113	frameshift	Exon 2 of 2	ENSP00000498702.1
GPR68	ENST00000531499.2	TSL:1	c.667_668delAA	p.Lys223GlyfsTer113	frameshift	Exon 2 of 2	ENSP00000434045.2
GPR68	ENST00000535815.5	TSL:1	c.667_668delAA	p.Lys223GlyfsTer113	frameshift	Exon 2 of 2	ENSP00000440797.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000470

AC:

AN:

212944

AF XY:

0.00000861

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1441932

Hom.:

AF XY:

0.00000279

AC XY:

AN XY:

716226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33204

American (AMR)

AF:

0.00

AC:

AN:

41804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25768

East Asian (EAS)

AF:

0.00

AC:

AN:

38986

South Asian (SAS)

AF:

0.0000238

AC:

AN:

84148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104990

Other (OTH)

AF:

0.00

AC:

AN:

59830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Amelogenesis imperfecta, hypomaturation type, IIa6

Pathogenic:1

Nov 21, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Amelogenesis imperfecta

Pathogenic:1

Aug 01, 2016

Leeds Amelogenesis Imperfecta Research Group, University of Leeds

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Predicted to remove two of the protein's transmembrane helices and two pH sensing histidine residues.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over