rs121918149

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000234071.8(PROC):c.226G>A(p.Val76Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PROC
ENST00000234071.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.315

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-127421438-G-A is Pathogenic according to our data. Variant chr2-127421438-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROC	NM_000312.4 linkuse as main transcript	c.226G>A	p.Val76Met	missense_variant	3/9	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8 linkuse as main transcript	c.226G>A	p.Val76Met	missense_variant	3/9	1	NM_000312.4	ENSP00000234071	P1	P04070-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152254

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250918

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.0000617

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:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

205

AN:

1461556

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727048

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:

0.000167

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Abnormal thrombosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Thrombophilia due to protein C deficiency, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 1992

- -

Cerebral palsy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Neurogenetics Research Program, University of Adelaide

Jun 10, 2021

- -

PROC-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

The PROC c.226G>A variant is predicted to result in the amino acid substitution p.Val76Met. This variant is also described with legacy nomenclature as p.Val34Met, and was reported along with a second potentially causative variant in three individuals from a single family with protein C deficiency (Long. 1992. PubMed ID: 1347706). This variant has also been reported in the heterozygous state in two patients with an unspecified bleeding, thrombotic, or platelet disorder (Wu. 2013. PubMed ID: 24051141; Table S3, Downes. 2019. PubMed ID: 31064749). In vitro functional studies found this variant results in decreased protein synthesis and reduced activation (Wu. 2013. PubMed ID: 24051141).This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D;.;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.23

T;T;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.60

D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.3

M;.;.;.;.

MutationTaster

Benign

0.0015

A;A;A;A

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.13

N;N;N;N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.10

.;T;T;T;.

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.95

P;.;.;.;P

Vest4

0.28

MVP

0.93

MPC

0.60

ClinPred

0.10

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

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