11-82849977-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRCP	NM_005040.4	c.688G>C	p.Gly230Arg	missense_variant	Exon 5 of 9	ENST00000313010.8	NP_005031.1
PRCP	NM_199418.4	c.751G>C	p.Gly251Arg	missense_variant	Exon 6 of 10		NP_955450.2
PRCP	NM_001319214.2	c.373G>C	p.Gly125Arg	missense_variant	Exon 4 of 8		NP_001306143.1
PRCP	XM_005274093.2	c.373G>C	p.Gly125Arg	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>C	p.Gly230Arg	missense_variant	Exon 5 of 9	1	NM_005040.4	ENSP00000317362.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;.;.;T;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;T
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.030	D;D;T;D;D;D;D
Sift4G	Uncertain	0.045	D;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

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: chr11-82561019;