chr19-49423264-A-T

Variant names:

• chr19-49423264-A-T
• rs1275064234
• NM_178449.4:c.76T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178449.4(PTH2):​c.76T>A​(p.Trp26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTH2 NM_178449.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.793

Genes affected

PTH2 (HGNC:30828): (parathyroid hormone 2) This gene encodes the precursor of a peptide hormone that shares sequence similarity with the parathyroid hormone. This gene is expressed in various regions of the brain where it plays a role in the release of pituitary hormones, anxiety and nociception. The encoded precursor protein is proteolytically processed to generate the biologically active neuropeptide. [provided by RefSeq, Jul 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39615285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTH2	NM_178449.4	c.76T>A	p.Trp26Arg	missense_variant	Exon 1 of 2	ENST00000270631.2	NP_848544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTH2	ENST00000270631.2	c.76T>A	p.Trp26Arg	missense_variant	Exon 1 of 2	1	NM_178449.4	ENSP00000270631.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 245370 AF XY: 0.00

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 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

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76T>A (p.W26R) alteration is located in exon 1 (coding exon 1) of the PTH2 gene. This alteration results from a T to A substitution at nucleotide position 76, causing the tryptophan (W) at amino acid position 26 to be replaced by an arginine (R). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.79
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Benign	0.072
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.042	D
Polyphen		0.90	P
Vest4		0.45
MutPred		0.43		Gain of solvent accessibility (P = 6e-04);
MVP		0.082
MPC		1.8
ClinPred		0.97	D
GERP RS		0.74
PromoterAI		-0.0046	Neutral
Varity_R		0.41
gMVP		0.26
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1275064234; hg19: chr19-49926521;