rs2298668

Variant names:

• chr11-82853252-T-G
• rs2229437
• NM_005040.4:c.336A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 37 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
PRCP	NM_005040.4	c.336A>C	p.Glu112Asp	missense_variant	Exon 3 of 9	ENST00000313010.8	NP_005031.1
PRCP	NM_199418.4	c.399A>C	p.Glu133Asp	missense_variant	Exon 4 of 10		NP_955450.2
PRCP	NM_001319214.2	c.21A>C	p.Glu7Asp	missense_variant	Exon 2 of 8		NP_001306143.1
PRCP	XM_005274093.2	c.21A>C	p.Glu7Asp	missense_variant	Exon 3 of 9		XP_005274150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRCP	ENST00000313010.8	c.336A>C	p.Glu112Asp	missense_variant	Exon 3 of 9	1	NM_005040.4	ENSP00000317362.3

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

GnomAD2 exomes AF: 0.155 AC: 38845 AN: 249904 AF XY: 0.160

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 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

African (AFR) AF: 0.123 AC: 4100 AN: 33344

American (AMR) AF: 0.103 AC: 4565 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5181 AN: 26060

East Asian (EAS) AF: 0.0977 AC: 3870 AN: 39592

South Asian (SAS) AF: 0.174 AC: 14930 AN: 85892

European-Finnish (FIN) AF: 0.152 AC: 8119 AN: 53376

Middle Eastern (MID) AF: 0.216 AC: 1244 AN: 5758

European-Non Finnish (NFE) AF: 0.177 AC: 196097 AN: 1109230

Other (OTH) AF: 0.177 AC: 10654 AN: 60246

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

African (AFR) AF: 0.127 AC: 5271 AN: 41506

American (AMR) AF: 0.134 AC: 2051 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3472

East Asian (EAS) AF: 0.105 AC: 546 AN: 5186

South Asian (SAS) AF: 0.179 AC: 864 AN: 4814

European-Finnish (FIN) AF: 0.163 AC: 1721 AN: 10568

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11797 AN: 67994

Other (OTH) AF: 0.176 AC: 370 AN: 2106

Alfa AF: 0.160 Hom.: 3314

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;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		0.36
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
Mutation Taster		=80/20	polymorphism (auto)

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