chr2-127421438-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PM1PM2PM5PP2BP4_Moderate

The NM_000312.4(PROC):​c.226G>T​(p.Val76Leu) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V76M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

PROC
NM_000312.4 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.315

Publications

6 publications found
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 Gene-Disease associations (from GenCC):
  • hereditary thrombophilia due to congenital protein C deficiency
    Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • thrombophilia due to protein C deficiency, autosomal dominant
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • thrombophilia due to protein C deficiency, autosomal recessive
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a chain Vitamin K-dependent protein C light chain (size 154) in uniprot entity PROC_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_000312.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: 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.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.88339 (below the threshold of 3.09). Trascript score misZ: 1.6095 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein C deficiency.
BP4
Computational evidence support a benign effect (MetaRNN=0.21555328).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PROCNM_000312.4 linkc.226G>T p.Val76Leu missense_variant Exon 3 of 9 ENST00000234071.8 NP_000303.1 P04070-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PROCENST00000234071.8 linkc.226G>T p.Val76Leu missense_variant Exon 3 of 9 1 NM_000312.4 ENSP00000234071.4 P04070-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
17
DANN
Benign
0.97
DEOGEN2
Uncertain
0.67
D;D;.;.;.
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.17
T;T;T;T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.22
T;T;T;T;T
MetaSVM
Uncertain
0.56
D
MutationAssessor
Benign
1.1
L;.;.;.;.
PhyloP100
0.32
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.62
N;N;N;N;N
REVEL
Benign
0.26
Sift
Benign
0.30
.;T;T;T;.
Sift4G
Benign
0.30
T;T;T;T;T
Polyphen
0.015
B;.;.;.;B
Vest4
0.24
MutPred
0.53
Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP
0.81
MPC
0.45
ClinPred
0.028
T
GERP RS
1.9
Varity_R
0.57
gMVP
0.93
Mutation Taster
=20/80
disease causing

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

Other links and lift over

dbSNP: rs121918149; hg19: chr2-128179014; API