2-208437835-A-T

Position:

• chr2-208437835-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005048.4(PTH2R):​c.365A>T​(p.Tyr122Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PTH2R NM_005048.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTH2R	NM_005048.4	c.365A>T	p.Tyr122Phe	missense_variant	4/13	ENST00000272847.7	NP_005039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTH2R	ENST00000272847.7	c.365A>T	p.Tyr122Phe	missense_variant	4/13	1	NM_005048.4	ENSP00000272847.2
PTH2R	ENST00000617735.4	c.32A>T	p.Tyr11Phe	missense_variant	4/13	2		ENSP00000482485.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2024

The c.365A>T (p.Y122F) alteration is located in exon 4 (coding exon 4) of the PTH2R gene. This alteration results from a A to T substitution at nucleotide position 365, causing the tyrosine (Y) at amino acid position 122 to be replaced by a phenylalanine (F). 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	Benign	0.26
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.6	.;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.86		.;Loss of ubiquitination at K117 (P = 0.0992);
MVP		0.23
MPC		0.23
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.54
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-209302560;