Variant chr2-208443391-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005048.4(PTH2R):c.553G>A(p.Val185Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,610,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

PTH2R
NM_005048.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 2.69

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_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016200095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH2R	NM_005048.4 linkuse as main transcript	c.553G>A	p.Val185Met	missense_variant	6/13	ENST00000272847.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH2R	ENST00000272847.7 linkuse as main transcript	c.553G>A	p.Val185Met	missense_variant	6/13	1	NM_005048.4	P1
PTH2R	ENST00000617735.4 linkuse as main transcript	c.220G>A	p.Val74Met	missense_variant	6/13	2

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000587

AC:

145

AN:

247166

Hom.:

AF XY:

0.000569

AC XY:

AN XY:

133660

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00887

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000401

Gnomad OTH exome

AF:

0.000999

GnomAD4 exome

AF:

0.000324

AC:

473

AN:

1457810

Hom.:

Cov.:

AF XY:

0.000317

AC XY:

230

AN XY:

725172

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000160

Gnomad4 ASJ exome

AF:

0.00712

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.000381

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000674

Hom.:

Bravo

AF:

0.000370

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000511

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign: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 04, 2022

The c.553G>A (p.V185M) alteration is located in exon 6 (coding exon 6) of the PTH2R gene. This alteration results from a G to A substitution at nucleotide position 553, causing the valine (V) at amino acid position 185 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PTH2R-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

T;T

Eigen

Benign

0.067

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.90

D;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.3

.;M

MutationTaster

Benign

0.63

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.4

.;N

REVEL

Benign

0.075

Sift

Benign

0.092

.;T

Sift4G

Benign

0.11

T;T

Polyphen

0.25

B;P

Vest4

0.36

MVP

0.14

MPC

0.099

ClinPred

0.044

GERP RS

4.2

Varity_R

0.13

gMVP

0.60

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