2-127427194-T-C

Position:

chr2-127427194-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000312.4(PROC):c.768T>C(p.Asp256=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,612,832 control chromosomes in the GnomAD database, including 81,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7054 hom., cov: 33)

Exomes 𝑓: 0.31 ( 74014 hom. )

Consequence

PROC
NM_000312.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: -1.57

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:

LOC105373608 (HGNC:):

LOC105373608 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-127427194-T-C is Benign according to our data. Variant chr2-127427194-T-C is described in ClinVar as [Benign]. Clinvar id is 255810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127427194-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.57 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROC	NM_000312.4 linkuse as main transcript	c.768T>C	p.Asp256=	synonymous_variant	8/9	ENST00000234071.8	NP_000303.1
LOC105373608	XR_007087228.1 linkuse as main transcript	n.2111A>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8 linkuse as main transcript	c.768T>C	p.Asp256=	synonymous_variant	8/9	1	NM_000312.4	ENSP00000234071	P1	P04070-1
PROC	ENST00000409048.1 linkuse as main transcript	c.870T>C	p.Asp290=	synonymous_variant	6/7	5		ENSP00000386679
PROC	ENST00000402125.2 linkuse as main transcript	c.121-1163T>C		intron_variant		2		ENSP00000384225

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45331

AN:

151956

Hom.:

7058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.323

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.280

Gnomad FIN

AF:

0.285

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.299

GnomAD3 exomes

AF:

0.272

AC:

67954

AN:

249518

Hom.:

10536

AF XY:

0.278

AC XY:

37537

AN XY:

135024

show subpopulations

Gnomad AFR exome

AF:

0.324

Gnomad AMR exome

AF:

0.170

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.00202

Gnomad SAS exome

AF:

0.283

Gnomad FIN exome

AF:

0.286

Gnomad NFE exome

AF:

0.327

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.312

AC:

455241

AN:

1460758

Hom.:

74014

Cov.:

AF XY:

0.312

AC XY:

226373

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.324

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.348

Gnomad4 EAS exome

AF:

0.00154

Gnomad4 SAS exome

AF:

0.292

Gnomad4 FIN exome

AF:

0.295

Gnomad4 NFE exome

AF:

0.330

Gnomad4 OTH exome

AF:

0.300

GnomAD4 genome

AF:

0.298

AC:

45340

AN:

152074

Hom.:

7054

Cov.:

AF XY:

0.291

AC XY:

21662

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.322

Gnomad4 AMR

AF:

0.231

Gnomad4 ASJ

AF:

0.343

Gnomad4 EAS

AF:

0.00425

Gnomad4 SAS

AF:

0.280

Gnomad4 FIN

AF:

0.285

Gnomad4 NFE

AF:

0.321

Gnomad4 OTH

AF:

0.296

Alfa

AF:

0.306

Hom.:

13114

Bravo

AF:

0.295

Asia WGS

AF:

0.136

AC:

476

AN:

3478

EpiCase

AF:

0.318

EpiControl

AF:

0.321

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

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: 34.828% in gnomAD_ExomesFounderPop) 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Thrombophilia due to protein C deficiency, autosomal dominant

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Thrombophilia due to protein C deficiency, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.94

DANN

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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