chr11-82838532-C-T

Position:

• chr11-82838532-C-T

Variant summary

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

The NM_005040.4(PRCP):​c.1129G>A​(p.Asp377Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: PRCP NM_005040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.797

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=0.04515639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRCP	NM_005040.4	c.1129G>A	p.Asp377Asn	missense_variant	8/9	ENST00000313010.8
PRCP	NM_199418.4	c.1192G>A	p.Asp398Asn	missense_variant	9/10
PRCP	NM_001319214.2	c.814G>A	p.Asp272Asn	missense_variant	7/8
PRCP	XM_005274093.2	c.814G>A	p.Asp272Asn	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRCP	ENST00000313010.8	c.1129G>A	p.Asp377Asn	missense_variant	8/9	1	NM_005040.4	P1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000307 AC: 77 AN: 251160 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135732

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000296 AC: 432 AN: 1461714 Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 215 AN XY: 727150

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74318

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000352 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The c.1192G>A (p.D398N) alteration is located in exon 9 (coding exon 9) of the PRCP gene. This alteration results from a G to A substitution at nucleotide position 1192, causing the aspartic acid (D) at amino acid position 398 to be replaced by an asparagine (N). 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	0.080
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.090	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.67	N;N
REVEL	Benign	0.040
Sift	Benign	0.75	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.15
MVP		0.32
MPC		0.028
ClinPred		0.019	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.81

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: rs138336049; hg19: chr11-82549574; COSMIC: COSV57291700; COSMIC: COSV57291700;