2-127418464-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000312.4(PROC):c.-50A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,289,384 control chromosomes in the GnomAD database, including 118,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15374 hom., cov: 32)
  • Exomes 𝑓: 0.42 (103340 hom.)
• Consequence: PROC NM_000312.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 1.21

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-127418464-A-T is Benign according to our data. Variant chr2-127418464-A-T is described in ClinVar as [Benign]. Clinvar id is 255808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127418464-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4	c.-50A>T		5_prime_UTR_variant	1/9	ENST00000234071.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8	c.-50A>T		5_prime_UTR_variant	1/9	1	NM_000312.4	P1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66581 AN: 151930 Hom.: 15366 Cov.: 32

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.436

GnomAD3 exomes AF: 0.381 AC: 52160 AN: 137010 Hom.: 10824 AF XY: 0.389 AC XY: 28936 AN XY: 74396

Gnomad AFR exome AF: 0.564

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.434

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.423 AC: 481127 AN: 1137336 Hom.: 103340 Cov.: 43 AF XY: 0.424 AC XY: 236561 AN XY: 557988

Gnomad4 AFR exome AF: 0.563

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.436

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.416

GnomAD4 genome AF: 0.438 AC: 66613 AN: 152048 Hom.: 15374 Cov.: 32 AF XY: 0.429 AC XY: 31886 AN XY: 74328

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.420

Gnomad4 FIN AF: 0.341

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.432

Alfa AF: 0.439 Hom.: 2728

Bravo AF: 0.440

Asia WGS AF: 0.272 AC: 951 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

Allele frequency is common in at least one population database (frequency: 57.719% in ExAC) based on the frequency threshold of 0.555% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	12
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1799810; hg19: chr2-128176040; COSMIC: COSV52166678; COSMIC: COSV52166678;