rs1333329860

Positions:

• chr2-127428766-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000312.4(PROC):​c.1212dup​(p.Pro405AlafsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PROC NM_000312.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.88

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]

LOC105373608 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-127428766-T-TG is Pathogenic according to our data. Variant chr2-127428766-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407370.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	c.1212dup	p.Pro405AlafsTer20	frameshift_variant	9/9	ENST00000234071.8	NP_000303.1
LOC105373608	XR_007087228.1	n.1041-503_1041-502insC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.1212dup	p.Pro405AlafsTer20	frameshift_variant	9/9	1	NM_000312.4	ENSP00000234071	P1
PROC	ENST00000402125.2	c.536dup	p.Pro180AlafsTer20	frameshift_variant	2/2	2		ENSP00000384225
PROC	ENST00000409048.1	c.1314dup	p.Pro439AlafsTer20	frameshift_variant	7/7	5		ENSP00000386679

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249134 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460634 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 23, 2022	PM2, PM3, PVS1_strong -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 03, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with protein C deficiency and venous thromboembolism (PMID: 7670104, 25039884), and neonatal purpura fulminans (PMID: 29356699). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1206_1207insG in the literature. ClinVar contains an entry for this variant (Variation ID: 407370). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the PROC gene (p.Pro405Alafs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acids of the PROC protein. -

Computational scores

Source: dbNSFP v4.3

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: rs1333329860; hg19: chr2-128186342;