Variant chr2-208437843-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005048.4(PTH2R):c.373T>A(p.Cys125Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,502 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: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PTH2R
NM_005048.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.73

Variant links:

Genes affected

PTH2R (HGNC:9609): (parathyroid hormone 2 receptor) The protein encoded by this gene is a member of the G-protein coupled receptor 2 family. This protein is a receptor for parathyroid hormone (PTH). This receptor is more selective in ligand recognition and has a more specific tissue distribution compared to parathyroid hormone receptor 1 (PTHR1). It is activated only by PTH and not by parathyroid hormone-like hormone (PTHLH) and is particularly abundant in brain and pancreas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

PTH2R links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH2R	NM_005048.4 linkuse as main transcript	c.373T>A	p.Cys125Ser	missense_variant	4/13	ENST00000272847.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH2R	ENST00000272847.7 linkuse as main transcript	c.373T>A	p.Cys125Ser	missense_variant	4/13	1	NM_005048.4	P1
PTH2R	ENST00000617735.4 linkuse as main transcript	c.40T>A	p.Cys14Ser	missense_variant	4/13	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251186

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135754

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461502

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727020

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

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

Dec 19, 2023

The c.373T>A (p.C125S) alteration is located in exon 4 (coding exon 4) of the PTH2R gene. This alteration results from a T to A substitution at nucleotide position 373, causing the cysteine (C) at amino acid position 125 to be replaced by a serine (S). 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

0.99

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.1

.;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-8.4

.;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.86

MutPred

0.95

.;Loss of catalytic residue at L126 (P = 0.0236);

MVP

0.46

MPC

0.25

ClinPred

1.0

GERP RS

5.1

Varity_R

0.71

gMVP

0.88

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