Variant 2-127418464-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 1.21

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 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.-50A>T		5_prime_UTR_variant	1/9	1	NM_000312.4	P1	P04070-1

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66581

AN:

151930

Hom.:

15366

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.424

AC XY:

236561

AN XY:

557988

show subpopulations

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.:

AF XY:

0.429

AC XY:

31886

AN XY:

74328

show subpopulations

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:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

Thrombophilia due to protein C deficiency, autosomal dominant

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over