11-82849977-C-T

Variant names:

• chr11-82849977-C-T
• rs140634119
• NM_005040.4:c.688G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005040.4(PRCP):​c.688G>A​(p.Gly230Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000495 in 1,547,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: PRCP NM_005040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

Genes affected

PRCP (HGNC:9344): (prolylcarboxypeptidase) This gene encodes a member of the peptidase S28 family of serine exopeptidases. The encoded preproprotein is proteolytically processed to generate the mature lysosomal prolylcarboxypeptidase. This enzyme cleaves C-terminal amino acids linked to proline in peptides such as angiotension II, III and des-Arg9-bradykinin. The cleavage occurs at acidic pH, but the enzyme activity is retained with some substrates at neutral pH. This enzyme has been shown to be an activator of the cell matrix-associated prekallikrein. The importance of angiotension II, one of the substrates of this enzyme, in regulating blood pressure and electrolyte balance suggests that this gene may be related to essential hypertension. A pseudogene of this gene has been identified on chromosome 2. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

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=0.056352735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRCP	NM_005040.4	c.688G>A	p.Gly230Ser	missense_variant	Exon 5 of 9	ENST00000313010.8	NP_005031.1
PRCP	NM_199418.4	c.751G>A	p.Gly251Ser	missense_variant	Exon 6 of 10		NP_955450.2
PRCP	NM_001319214.2	c.373G>A	p.Gly125Ser	missense_variant	Exon 4 of 8		NP_001306143.1
PRCP	XM_005274093.2	c.373G>A	p.Gly125Ser	missense_variant	Exon 5 of 9		XP_005274150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRCP	ENST00000313010.8	c.688G>A	p.Gly230Ser	missense_variant	Exon 5 of 9	1	NM_005040.4	ENSP00000317362.3

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000189 AC: 41 AN: 216488 Hom.: 0 AF XY: 0.000211 AC XY: 25 AN XY: 118302

Gnomad AFR exome AF: 0.000233

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000386

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000355

Gnomad OTH exome AF: 0.000203

GnomAD4 exome AF: 0.000527 AC: 736 AN: 1395772 Hom.: 0 Cov.: 30 AF XY: 0.000489 AC XY: 339 AN XY: 693936

Gnomad4 AFR exome AF: 0.0000986

Gnomad4 AMR exome AF: 0.0000530

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000392

Gnomad4 FIN exome AF: 0.000116

Gnomad4 NFE exome AF: 0.000633

Gnomad4 OTH exome AF: 0.000701

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74386

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000291

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.751G>A (p.G251S) alteration is located in exon 6 (coding exon 6) of the PRCP gene. This alteration results from a G to A substitution at nucleotide position 751, causing the glycine (G) at amino acid position 251 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	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.56
DEOGEN2	Benign	0.17	T;.;.;.;T;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.056	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.25	N;.;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.49	T;T;T;T;T;T;T
Sift4G	Benign	0.67	T;T;.;.;.;.;.
Polyphen		0.035	B;.;.;.;.;.;.
Vest4		0.40
MVP		0.18
MPC		0.029
ClinPred		0.073	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.83

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: rs140634119; hg19: chr11-82561019;