Variant 2-127423296-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000312.4(PROC):c.423G>T(p.Ser141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,549,898 control chromosomes in the GnomAD database, including 362,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 36480 hom., cov: 36)

Exomes 𝑓: 0.68 ( 325588 hom. )

Consequence

PROC
NM_000312.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.81

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 2-127423296-G-T is Benign according to our data. Variant chr2-127423296-G-T is described in ClinVar as [Benign]. Clinvar id is 255809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127423296-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.81 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.743 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.423G>T	p.Ser141=	synonymous_variant	6/9	ENST00000234071.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8 linkuse as main transcript	c.423G>T	p.Ser141=	synonymous_variant	6/9	1	NM_000312.4	P1	P04070-1

Frequencies

GnomAD3 genomes

AF:

0.692

AC:

105153

AN:

152022

Hom.:

36471

Cov.:

show subpopulations

Gnomad AFR

AF:

0.719

Gnomad AMI

AF:

0.797

Gnomad AMR

AF:

0.754

Gnomad ASJ

AF:

0.692

Gnomad EAS

AF:

0.572

Gnomad SAS

AF:

0.521

Gnomad FIN

AF:

0.685

Gnomad MID

AF:

0.682

Gnomad NFE

AF:

0.682

Gnomad OTH

AF:

0.693

GnomAD3 exomes

AF:

0.678

AC:

100470

AN:

148168

Hom.:

34891

AF XY:

0.661

AC XY:

52156

AN XY:

78878

show subpopulations

Gnomad AFR exome

AF:

0.721

Gnomad AMR exome

AF:

0.833

Gnomad ASJ exome

AF:

0.711

Gnomad EAS exome

AF:

0.562

Gnomad SAS exome

AF:

0.522

Gnomad FIN exome

AF:

0.677

Gnomad NFE exome

AF:

0.686

Gnomad OTH exome

AF:

0.686

GnomAD4 exome

AF:

0.680

AC:

951060

AN:

1397762

Hom.:

325588

Cov.:

AF XY:

0.675

AC XY:

465408

AN XY:

689444

show subpopulations

Gnomad4 AFR exome

AF:

0.711

Gnomad4 AMR exome

AF:

0.820

Gnomad4 ASJ exome

AF:

0.709

Gnomad4 EAS exome

AF:

0.642

Gnomad4 SAS exome

AF:

0.522

Gnomad4 FIN exome

AF:

0.685

Gnomad4 NFE exome

AF:

0.687

Gnomad4 OTH exome

AF:

0.674

GnomAD4 genome

AF:

0.691

AC:

105200

AN:

152136

Hom.:

36480

Cov.:

AF XY:

0.688

AC XY:

51165

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.719

Gnomad4 AMR

AF:

0.754

Gnomad4 ASJ

AF:

0.692

Gnomad4 EAS

AF:

0.572

Gnomad4 SAS

AF:

0.520

Gnomad4 FIN

AF:

0.685

Gnomad4 NFE

AF:

0.682

Gnomad4 OTH

AF:

0.686

Alfa

AF:

0.696

Hom.:

19198

Bravo

AF:

0.704

Asia WGS

AF:

0.548

AC:

1905

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

Thrombophilia due to protein C deficiency, autosomal dominant

Benign:3

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

not provided

Benign:2

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 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

-0.73

CADD

Benign

3.3

DANN

Benign

0.77

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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