dbSNP rs2069921: PROC:c.238-655G>A (chr2-127422262-G-A) – 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.238-655G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 152,150 control chromosomes in the GnomAD database, including 40,357 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 0.73 ( 40357 hom., cov: 33)

Consequence

PROC
NM_000312.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.839

Publications

7 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=-0.87).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4 link	c.238-655G>A		intron_variant	Intron 3 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.238-655G>A		intron_variant	Intron 3 of 8	1	NM_000312.4	ENSP00000234071.4		P04070-1

Frequencies

GnomAD3 genomes

AF:

0.727

AC:

110529

AN:

152032

Hom.:

40348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.728

Gnomad AMI

AF:

0.812

Gnomad AMR

AF:

0.791

Gnomad ASJ

AF:

0.812

Gnomad EAS

AF:

0.573

Gnomad SAS

AF:

0.536

Gnomad FIN

AF:

0.711

Gnomad MID

AF:

0.744

Gnomad NFE

AF:

0.734

Gnomad OTH

AF:

0.732

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

GnomAD4 genome

AF:

0.727

AC:

110577

AN:

152150

Hom.:

40357

Cov.:

AF XY:

0.722

AC XY:

53703

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.727

AC:

30187

AN:

41514

American (AMR)

AF:

0.791

AC:

12110

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.812

AC:

2818

AN:

3472

East Asian (EAS)

AF:

0.573

AC:

2953

AN:

5154

South Asian (SAS)

AF:

0.535

AC:

2578

AN:

4822

European-Finnish (FIN)

AF:

0.711

AC:

7528

AN:

10590

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.734

AC:

49919

AN:

67980

Other (OTH)

AF:

0.723

AC:

1528

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1600

3200

4799

6399

7999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.742

Hom.:

5591

Bravo

AF:

0.738

Asia WGS

AF:

0.557

AC:

1938

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.10

(source)

DANN

Benign

0.62

PhyloP100

-0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

0.99

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

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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