Genetic Variant PROC:c.70+386T>C (chr2-127420398-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000312.4(PROC):c.70+386T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 151,970 control chromosomes in the GnomAD database, including 20,719 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.52 ( 20719 hom., cov: 32)

Consequence

PROC
NM_000312.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.95

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

hereditary thrombophilia due to congenital protein C deficiency
Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
thrombophilia due to protein C deficiency, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
thrombophilia due to protein C deficiency, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

PROC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4 link	c.70+386T>C		intron_variant	Intron 2 of 8	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.70+386T>C		intron_variant	Intron 2 of 8	1	NM_000312.4	ENSP00000234071.4		P04070-1

Frequencies

GnomAD3 genomes

AF:

0.517

AC:

78473

AN:

151852

Hom.:

20711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.498

Gnomad AMI

AF:

0.447

Gnomad AMR

AF:

0.413

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.264

Gnomad SAS

AF:

0.653

Gnomad FIN

AF:

0.550

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.557

Gnomad OTH

AF:

0.526

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.517

AC:

78525

AN:

151970

Hom.:

20719

Cov.:

AF XY:

0.514

AC XY:

38193

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.498

AC:

20634

AN:

41424

American (AMR)

AF:

0.412

AC:

6302

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.510

AC:

1767

AN:

3468

East Asian (EAS)

AF:

0.263

AC:

1359

AN:

5160

South Asian (SAS)

AF:

0.653

AC:

3149

AN:

4822

European-Finnish (FIN)

AF:

0.550

AC:

5804

AN:

10552

Middle Eastern (MID)

AF:

0.554

AC:

163

AN:

294

European-Non Finnish (NFE)

AF:

0.557

AC:

37820

AN:

67950

Other (OTH)

AF:

0.532

AC:

1121

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1922

3845

5767

7690

9612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.483

Hom.:

3097

Bravo

AF:

0.501

Asia WGS

AF:

0.474

AC:

1649

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.12

(source)

DANN

Benign

0.14

PhyloP100

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over