2-127418464-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001375607.1(PROC):c.18A>T(p.Arg6Arg) variant causes a synonymous 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_001375607.1 synonymous

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PROC	NM_000312.4 link	c.-50A>T		5_prime_UTR_variant	Exon 1 of 9	ENST00000234071.8	NP_000303.1	P04070-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8 link	c.-50A>T		5_prime_UTR_variant	Exon 1 of 9	1	NM_000312.4	ENSP00000234071.4		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

GnomAD2 exomes

AF:

0.381

AC:

52160

AN:

137010

AF XY:

0.389

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 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

African (AFR)

AF:

0.563

AC:

13745

AN:

24412

American (AMR)

AF:

0.243

AC:

6862

AN:

28266

Ashkenazi Jewish (ASJ)

AF:

0.495

AC:

7887

AN:

15940

East Asian (EAS)

AF:

0.168

AC:

2151

AN:

12840

South Asian (SAS)

AF:

0.436

AC:

33233

AN:

76198

European-Finnish (FIN)

AF:

0.358

AC:

4676

AN:

13062

Middle Eastern (MID)

AF:

0.493

AC:

2169

AN:

4402

European-Non Finnish (NFE)

AF:

0.427

AC:

393110

AN:

920686

Other (OTH)

AF:

0.416

AC:

17294

AN:

41530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

15249

30498

45748

60997

76246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.438

AC:

66613

AN:

152048

Hom.:

15374

Cov.:

AF XY:

0.429

AC XY:

31886

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.561

AC:

23250

AN:

41442

American (AMR)

AF:

0.322

AC:

4929

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.497

AC:

1727

AN:

3472

East Asian (EAS)

AF:

0.174

AC:

898

AN:

5168

South Asian (SAS)

AF:

0.420

AC:

2023

AN:

4818

European-Finnish (FIN)

AF:

0.341

AC:

3604

AN:

10582

Middle Eastern (MID)

AF:

0.476

AC:

140

AN:

294

European-Non Finnish (NFE)

AF:

0.422

AC:

28687

AN:

67962

Other (OTH)

AF:

0.432

AC:

912

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1879

3758

5638

7517

9396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

1.2

PromoterAI

-0.060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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2-127418464-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over