2-127423123-T-C

Position:

• chr2-127423123-T-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.352T>C​(p.Phe118Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000894 in 1,454,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.97

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 (HGNC:):

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, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROC	NM_000312.4	c.352T>C	p.Phe118Leu	missense_variant	5/9	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.352T>C	p.Phe118Leu	missense_variant	5/9	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000894 AC: 13 AN: 1454306 Hom.: 0 Cov.: 36 AF XY: 0.00000830 AC XY: 6 AN XY: 722840

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 Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 12, 2022	ClinVar contains an entry for this variant (Variation ID: 469122). An algorithm developed specifically for the PROC gene suggests that this missense change is likely to be deleterious (PMID: 17152060). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is also known as p.Phe76Leu. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 118 of the PROC protein (p.Phe118Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with protein C deficiency and/or protein C deficiency type I (PMID: 1868249, 17152060, 32717757). It has also been observed to segregate with disease in related individuals. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	Jan 01, 2020	- -

Thromboembolism;C0149871:Deep venous thrombosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	.;D;T;.
Sift4G	Uncertain	0.052	T;D;T;T
Polyphen		0.85	P;.;.;P
Vest4		0.48
MutPred		0.79		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.97
MPC		0.83
ClinPred		0.97	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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

Other links and lift over

dbSNP: rs1553424043; hg19: chr2-128180699;