chr2-127426114-C-T

Position:

chr2-127426114-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_000312.4(PROC):c.565C>T(p.Arg189Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,004 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00046 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

PROC
NM_000312.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: -0.0360

Variant links:

Genes affected

PROC (HGNC:9451): (protein C, inactivator of coagulation factors Va and VIIIa) This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

PROC links:

LOC105373608 (HGNC:):

LOC105373608 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000312.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0060937107).

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4 linkuse as main transcript	c.565C>T	p.Arg189Trp	missense_variant	7/9	ENST00000234071.8
LOC105373608	XR_007087228.1 linkuse as main transcript	n.3191G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8 linkuse as main transcript	c.565C>T	p.Arg189Trp	missense_variant	7/9	1	NM_000312.4	P1	P04070-1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00905

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000752

AC:

189

AN:

251346

Hom.:

AF XY:

0.000751

AC XY:

102

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00805

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000208

AC:

304

AN:

1461792

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

160

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00390

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000460

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00888

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000219

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000717

AC:

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant

Pathogenic:2Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PROC c.565C>T (p.Arg189Trp) variant is reported as a cause of type II protein C deficiency that produces a protein with decreased functional activity and a relatively normal antigen level. Heterozygous carriers of pathogenic variants in the PROC gene are said to have mild protein C deficiency which is often asymptomatic, but may involve recurrent venous thrombosis. Tang et al. (2012) identified the p.Arg189Trp variant in 17 of 36 individuals diagnosed with hereditary protein C deficiency. All 17 individuals were heterozygous for the variant, had repeated low plasma protein C activity, and a clinical history of deep vein thrombosis (DVT). The authors then evaluated the p.Arg189Trp variant in a case-control study and found the variant in 59 of 1003 individuals with venous thrombosis. The authors conclude that the p.Arg189Trp variant is the most frequent pathogenic variant associated with protein C deficiency in the Chinese population and a significant risk factor for venous thrombosis. The p.Arg189Trp variant has also been reported in more recent study in which it is found in one individual in a compound heterozygous state (Kim et al. 2014). The p.Arg189Trp variant is reported in a heterozygous state in nine out of 4031 controls and at a frequency of 0.01984 in the East Asian population of the Exome Aggregation Consortium including two homozygotes. This allele frequency is high but is consistent with the disease prevalence. Based on the evidence from the literature, the p.Arg189Trp variant is classified as pathogenic for protein C deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 189 of the PROC protein (p.Arg189Trp). This variant is present in population databases (rs146922325, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with venous thromboembolism and PROC-deficiency (PMID: 7482420, 22545135, 22817391, 22944127, 23332921, 24028705, 24162787, 28111891, 32717757). ClinVar contains an entry for this variant (Variation ID: 161342). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects PROC function (PMID: 23389250). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 17, 2019	- -

Reduced protein C activity

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Thrombophilia 3 due to protein C deficiency

Pathogenic:1

Established risk allele, no assertion criteria provided

research

Department of Pathology and Laboratory Medicine, Sinai Health System

The PROC c.565C>T (p.Arg189Trp) (also known as the p.Arg147Trp variant in the literature) has been identified as a common variant causing protein C deficiency among East Asian populations, with a reported frequency of 27.8% in the protein C deficient Chinese population (Ding_2014_PMID:23389250). The variant has been identified in numerous homozygous and heterozygous individuals with deep vein thrombosis (DVT) and protein C deficiency (Duc Do_2021_PMID:32964666, Tang_2012_PMID:22545135, Li_2018_PMID:30210609, Ding_2014_PMID:23389250, Tang_2012_PMID:22817391). One case-control study in a Chinese DVT patient population identified the p.Arg189Trp variant at a frequency of 5.88% in the DVT population compared to 0.87% in healthy controls, and identified that first-degree relatives of affected patients who harbour the p.R189W variant have an 8.8-fold increased risk of venous thrombosis (Tang_2012_PMID:22817391, Tang_2012_PMID:22545135). The variant was identified in dbSNP (ID: rs146922325) and ClinVar (classified as uncertain by Invitae, Mendelics and 1 other submitter, pathogenic by Illumina, and likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 202 of 282736 chromosomes (2 homozygous) at a frequency of 0.0007144, and was observed at the highest frequency in the East Asian population in 156 of 19950 chromosomes (freq: 0.007820) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Arg189 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI) predict an uncertain effect on splicing. The p.Arg189Trp variant has shown to exhibit ~3 fold lower affinity for binding the EPCR transmembrane receptor (Ding_2014_PMID:23389250). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic – risk factor for thrombophilia due to protein C deficiency. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.64

D;.;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.72

T;T;T

MetaRNN

Benign

0.0061

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.5

L;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.1

N;D;N

REVEL

Uncertain

0.58

Sift

Benign

0.10

.;T;.

Sift4G

Benign

0.064

T;T;T

Polyphen

0.18

B;.;B

Vest4

0.12

MVP

0.91

MPC

0.47

ClinPred

0.0091

GERP RS

-0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over