2-127419968-T-C

Variant names:

• chr2-127419968-T-C
• NM_000312.4:c.26T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000312.4(PROC):​c.26T>C​(p.Leu9Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.26T>C	p.Leu9Pro	missense_variant	Exon 2 of 9	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.26T>C	p.Leu9Pro	missense_variant	Exon 2 of 9	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant Uncertain:1

Mar 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 9 of the PROC protein (p.Leu9Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with protein C deficiency (PMID: 7951255, 22951146, 25393254). This variant is also known as -34 Leu->Pro, Leu-34Pro, p.Leu8(-34)Pro. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PROC function (PMID: 25393254). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.76	D;T;.;.;.
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.68	T;T;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	.;D;D;D;.
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.081	B;.;.;.;D
Vest4		0.84
MutPred		0.80		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.96
MPC		1.6
ClinPred		0.85	D
GERP RS		4.6
Varity_R		0.89
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-128177544;