rs371071104
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000312.4(PROC):c.580C>T(p.Arg194Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
PROC
NM_000312.4 missense
NM_000312.4 missense
Scores
4
8
7
Clinical Significance
Conservation
PhyloP100: 0.309
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PROC | NM_000312.4 | c.580C>T | p.Arg194Cys | missense_variant | 7/9 | ENST00000234071.8 | NP_000303.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PROC | ENST00000234071.8 | c.580C>T | p.Arg194Cys | missense_variant | 7/9 | 1 | NM_000312.4 | ENSP00000234071.4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251394Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135894
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GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461812Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727198
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74448
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Thrombophilia due to protein C deficiency, autosomal dominant Uncertain:2
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 13, 2021 | This sequence change replaces arginine with cysteine at codon 194 of the PROC protein (p.Arg194Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs371071104, ExAC 0.009%). This missense change has been observed in individuals with protein C deficiency (PMID: 7482420, 27517348). 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 disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PROC function (PMID: 27517348). 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. - |
Thrombophilia due to protein C deficiency, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 04, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Pathogenic
.;D;.
Sift4G
Uncertain
D;D;D
Polyphen
D;.;P
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at