NM_005040.4:c.681G>C

Variant names:

• chr11-82849984-C-G
• rs745466670
• NM_005040.4:c.681G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005040.4(PRCP):​c.681G>C​(p.Arg227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRCP NM_005040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.961

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29524827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRCP	NM_005040.4	c.681G>C	p.Arg227Ser	missense_variant	Exon 5 of 9	ENST00000313010.8	NP_005031.1
PRCP	NM_199418.4	c.744G>C	p.Arg248Ser	missense_variant	Exon 6 of 10		NP_955450.2
PRCP	NM_001319214.2	c.366G>C	p.Arg122Ser	missense_variant	Exon 4 of 8		NP_001306143.1
PRCP	XM_005274093.2	c.366G>C	p.Arg122Ser	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.681G>C	p.Arg227Ser	missense_variant	Exon 5 of 9	1	NM_005040.4	ENSP00000317362.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000454 AC: 1 AN: 220120 Hom.: 0 AF XY: 0.00000832 AC XY: 1 AN XY: 120140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000363

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.744G>C (p.R248S) alteration is located in exon 6 (coding exon 6) of the PRCP gene. This alteration results from a G to C substitution at nucleotide position 744, causing the arginine (R) at amino acid position 248 to be replaced by a serine (S). 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	0.20
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.;.;T;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	T;T;T;T;T;T;T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.26	N;.;.;.;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.39	T;T;T;T;T;T;T
Sift4G	Benign	0.45	T;T;.;.;.;.;.
Polyphen		0.0050	B;.;.;.;.;.;.
Vest4		0.27
MutPred		0.54		Gain of disorder (P = 0.0418);.;.;.;.;.;.;
MVP		0.98
MPC		0.029
ClinPred		0.098	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.57

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: rs745466670; hg19: chr11-82561026;