chr20-5302075-T-C

Variant summary

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

The NM_144773.4(PROKR2):​c.1120A>G​(p.Thr374Ala) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PROKR2
NM_144773.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44
Variant links:
Genes affected
PROKR2 (HGNC:15836): (prokineticin receptor 2) Prokineticins are secreted proteins that can promote angiogenesis and induce strong gastrointestinal smooth muscle contraction. The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor for prokineticins. The encoded protein is similar in sequence to GPR73, another G protein-coupled receptor for prokineticins. [provided by RefSeq, Jul 2008]

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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=0.026857376).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PROKR2NM_144773.4 linkuse as main transcriptc.1120A>G p.Thr374Ala missense_variant 3/3 ENST00000678254.1 NP_658986.1
PROKR2XM_017027646.2 linkuse as main transcriptc.1120A>G p.Thr374Ala missense_variant 3/4 XP_016883135.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PROKR2ENST00000678254.1 linkuse as main transcriptc.1120A>G p.Thr374Ala missense_variant 3/3 NM_144773.4 ENSP00000504128 P1
PROKR2ENST00000217270.4 linkuse as main transcriptc.1120A>G p.Thr374Ala missense_variant 3/31 ENSP00000217270 P1
PROKR2ENST00000678059.1 linkuse as main transcriptc.1012A>G p.Thr338Ala missense_variant 3/3 ENSP00000503366

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 08, 2022This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 374 of the PROKR2 protein (p.Thr374Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PROKR2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.048
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
12
DANN
Benign
0.095
DEOGEN2
Benign
0.059
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.040
N
LIST_S2
Benign
0.028
T
M_CAP
Benign
0.0058
T
MetaRNN
Benign
0.027
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-2.0
N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.30
N
REVEL
Benign
0.12
Sift
Benign
1.0
T
Sift4G
Benign
0.64
T
Polyphen
0.0
B
Vest4
0.033
MutPred
0.23
Loss of phosphorylation at T374 (P = 0.051);
MVP
0.40
ClinPred
0.034
T
GERP RS
4.3
Varity_R
0.032
gMVP
0.29

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: chr20-5282721; API