NM_005040.4:c.688G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005040.4(PRCP):​c.688G>C​(p.Gly230Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,395,774 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G230S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PRCP NM_005040.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.81
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005040.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRCP	NM_005040.4	MANE Select	c.688G>C	p.Gly230Arg	missense	Exon 5 of 9	NP_005031.1	P42785-1
	PRCP	NM_199418.4		c.751G>C	p.Gly251Arg	missense	Exon 6 of 10	NP_955450.2	P42785-2
	PRCP	NM_001319214.2		c.373G>C	p.Gly125Arg	missense	Exon 4 of 8	NP_001306143.1	B7Z7Q6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRCP	ENST00000313010.8	TSL:1 MANE Select	c.688G>C	p.Gly230Arg	missense	Exon 5 of 9	ENSP00000317362.3	P42785-1
	PRCP	ENST00000393399.6	TSL:2	c.751G>C	p.Gly251Arg	missense	Exon 6 of 10	ENSP00000377055.2	P42785-2
	PRCP	ENST00000949391.1		c.688G>C	p.Gly230Arg	missense	Exon 5 of 9	ENSP00000619450.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1395774 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 693938

African (AFR) AF: 0.00 AC: 0 AN: 30416

American (AMR) AF: 0.00 AC: 0 AN: 37728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24592

East Asian (EAS) AF: 0.00 AC: 0 AN: 35378

South Asian (SAS) AF: 0.00 AC: 0 AN: 76590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077070

Other (OTH) AF: 0.00 AC: 0 AN: 57028

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.8
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.27
Sift	Benign	0.030	D
Sift4G	Uncertain	0.045	D
Polyphen		0.96	D
Vest4		0.68
MutPred		0.68		Loss of ubiquitination at K228 (P = 0.0328)
MVP		0.38
MPC		0.19
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.66
gMVP		0.93
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs140634119; hg19: chr11-82561019;