rs121918145

Positions:

chr2-127426178-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The ENST00000234071.8(PROC):c.629C>T(p.Pro210Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P210S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PROC
ENST00000234071.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 2.40

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a chain Vitamin K-dependent protein C heavy chain (size 261) in uniprot entity PROC_HUMAN there are 67 pathogenic changes around while only 11 benign (86%) in ENST00000234071.8

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-127426178-C-T is Pathogenic according to our data. Variant chr2-127426178-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 661.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROC	NM_000312.4 linkuse as main transcript	c.629C>T	p.Pro210Leu	missense_variant	7/9	ENST00000234071.8	NP_000303.1
LOC105373608	XR_007087228.1 linkuse as main transcript	n.3127G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8 linkuse as main transcript	c.629C>T	p.Pro210Leu	missense_variant	7/9	1	NM_000312.4	ENSP00000234071	P1	P04070-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251414

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 15, 2018	The PROC c.629C>T (p.Pro210Leu) missense variant has been reported in four studies and is found in a total of 12 individuals with protein C deficiency including two in a homozygous state, one in a compound heterozygous state, and at least nine in a heterozygous state (Conard et al. 1992; Reitsma et al. 1995; David et al. 2011; Kim et al. 2014). One homozygous patient had at least six unaffected family members who carried the variant in a heterozygous state (Conard et al. 1992). Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele only so the variant is presumed to be rare. Based on the evidence, the p.Pro210Leu variant is classified as a variant of unknown significance but suspicious of pathogenicity for protein C deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2021	For these reasons, this variant has been classified as Pathogenic. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with protein C deficiency (PMID: 1347608, 18573519, 21621249, 7482420, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as 6216C>T; Pro168Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 661). This variant is present in population databases (rs121918145, ExAC 0.002%). This sequence change replaces proline with leucine at codon 210 of the PROC protein (p.Pro210Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Thrombophilia due to protein C deficiency, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 21, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.0

M;.

MutationTaster

Benign

0.000057

A;A;A;A

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.54

Sift4G

Benign

0.50

T;T

Polyphen

0.97

D;B

Vest4

0.37

MutPred

0.49

.;Loss of disorder (P = 0.1093);

MVP

0.95

MPC

0.79

ClinPred

0.61

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.72

gMVP

0.89

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

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