NM_001177676.2:c.386_835del

Variant names:

• chr14-91234215-CAGTTGAAGCTGGTGAGCAGGAGGGAGAAGTGGTAGGCGTTGAAAACGCCCTTGGCGAAGTCGCAGCTGGCCTCCCAGACGCTGCGCACCAGCAGCAACACGTGGTAGGGCAGGAAGCAGGCCAGGAAGATGACCACGGTGCTGAGCACCAGCCGCTGGATCTGGTCCTTGCGGCTCTTCTGGGTGCCGTGGCTCCGGCGCACGGCGCGCAGGATGCCCTGGTAGGACGCCAGCAGCAGGCAGATGGGGAAGAGGAAGCCCACCAGGAAGCGGTAGTAGTTGATGGCGCGCTGCCATGCCTGGATGGGGTAGTGCTCAAAGCACACGCGGTGCTGGTTCTCGTCCTCGATGACCTCCTCGTGCATCAGGAAGTAGATGCTGGTCAGCAGCTCCTTGGCCCAGATGACCACGCTGACGCCGACGGCCGCCTTCAGGGTCCGGAACTGGTGGA-C
• rs1555409827
• NM_001177676.2:c.386_835del

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_001177676.2(GPR68):​c.386_835del​(p.Phe129_Asn278del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPR68 NM_001177676.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001177676.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 14-91234215-CAGTTGAAGCTGGTGAGCAGGAGGGAGAAGTGGTAGGCGTTGAAAACGCCCTTGGCGAAGTCGCAGCTGGCCTCCCAGACGCTGCGCACCAGCAGCAACACGTGGTAGGGCAGGAAGCAGGCCAGGAAGATGACCACGGTGCTGAGCACCAGCCGCTGGATCTGGTCCTTGCGGCTCTTCTGGGTGCCGTGGCTCCGGCGCACGGCGCGCAGGATGCCCTGGTAGGACGCCAGCAGCAGGCAGATGGGGAAGAGGAAGCCCACCAGGAAGCGGTAGTAGTTGATGGCGCGCTGCCATGCCTGGATGGGGTAGTGCTCAAAGCACACGCGGTGCTGGTTCTCGTCCTCGATGACCTCCTCGTGCATCAGGAAGTAGATGCTGGTCAGCAGCTCCTTGGCCCAGATGACCACGCTGACGCCGACGGCCGCCTTCAGGGTCCGGAACTGGTGGA-C is Pathogenic according to our data. Variant chr14-91234215-CAGTTGAAGCTGGTGAGCAGGAGGGAGAAGTGGTAGGCGTTGAAAACGCCCTTGGCGAAGTCGCAGCTGGCCTCCCAGACGCTGCGCACCAGCAGCAACACGTGGTAGGGCAGGAAGCAGGCCAGGAAGATGACCACGGTGCTGAGCACCAGCCGCTGGATCTGGTCCTTGCGGCTCTTCTGGGTGCCGTGGCTCCGGCGCACGGCGCGCAGGATGCCCTGGTAGGACGCCAGCAGCAGGCAGATGGGGAAGAGGAAGCCCACCAGGAAGCGGTAGTAGTTGATGGCGCGCTGCCATGCCTGGATGGGGTAGTGCTCAAAGCACACGCGGTGCTGGTTCTCGTCCTCGATGACCTCCTCGTGCATCAGGAAGTAGATGCTGGTCAGCAGCTCCTTGGCCCAGATGACCACGCTGACGCCGACGGCCGCCTTCAGGGTCCGGAACTGGTGGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 268084.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR68	NM_001177676.2	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	ENST00000650645.1	NP_001171147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR68	ENST00000650645.1	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2		NM_001177676.2	ENSP00000498702.1
GPR68	ENST00000531499.2	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	1		ENSP00000434045.2
GPR68	ENST00000535815.5	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	1		ENSP00000440797.1
GPR68	ENST00000529102.1	c.386_835del	p.Phe129_Asn278del	disruptive_inframe_deletion	Exon 2 of 2	1		ENSP00000432740.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

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

450bp in-frame deletion predicted to delete 4 of the 7 transmembrane helices and to remove 3 of the 6 histidines crucial to the pH sensitivity or structure of the protein -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555409827; hg19: chr14-91700559;