rs2298668

Positions:

• chr11-82853252-T-G
• chr11-82853252-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005040.4(PRCP):​c.336A>C​(p.Glu112Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,610,152 control chromosomes in the GnomAD database, including 23,998 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (1894 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22104 hom.)
• Consequence: PRCP NM_005040.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.362

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016741753).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRCP	NM_005040.4	c.336A>C	p.Glu112Asp	missense_variant	3/9	ENST00000313010.8	NP_005031.1
PRCP	NM_199418.4	c.399A>C	p.Glu133Asp	missense_variant	4/10		NP_955450.2
PRCP	NM_001319214.2	c.21A>C	p.Glu7Asp	missense_variant	2/8		NP_001306143.1
PRCP	XM_005274093.2	c.21A>C	p.Glu7Asp	missense_variant	3/9		XP_005274150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRCP	ENST00000313010.8	c.336A>C	p.Glu112Asp	missense_variant	3/9	1	NM_005040.4	ENSP00000317362	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23485 AN: 152020 Hom.: 1877 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.155 AC: 38845 AN: 249904 Hom.: 3318 AF XY: 0.160 AC XY: 21633 AN XY: 135090

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.0969

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.171 AC: 248760 AN: 1458012 Hom.: 22104 Cov.: 31 AF XY: 0.171 AC XY: 123940 AN XY: 725350

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.0977

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.155 AC: 23537 AN: 152140 Hom.: 1894 Cov.: 32 AF XY: 0.151 AC XY: 11229 AN XY: 74374

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.176

Alfa AF: 0.164 Hom.: 1821

Bravo AF: 0.153

TwinsUK AF: 0.177 AC: 656

ALSPAC AF: 0.170 AC: 655

ESP6500AA AF: 0.128 AC: 565

ESP6500EA AF: 0.180 AC: 1545

ExAC AF: 0.158 AC: 19185

Asia WGS AF: 0.183 AC: 636 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.192

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;.;T;T;T;.;.;T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.0021	P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.057	T;T;.;.;.;.;.;.;.;.;T;.
Polyphen		0.0010	B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.21
MPC		0.047
ClinPred		0.037	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.66

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: rs2229437; hg19: chr11-82564294; COSMIC: COSV57287858;