Genetic Variant PROC:c.-21-121C>T (chr2-127419801-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001375602.1(PROC):c.47-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,552,480 control chromosomes in the GnomAD database, including 260,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 22501 hom., cov: 33)

Exomes 𝑓: 0.58 ( 238240 hom. )

Consequence

PROC
NM_001375602.1 splice_region, intron

Scores

Splicing: ADA: 0.00007462

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.301

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 was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 2-127419801-C-T is Benign according to our data. Variant chr2-127419801-C-T is described in ClinVar as [Benign]. Clinvar id is 1220858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4 link	c.-21-121C>T		intron_variant	Intron 1 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.-21-121C>T		intron_variant	Intron 1 of 8	1	NM_000312.4	ENSP00000234071.4		P04070-1

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79427

AN:

151976

Hom.:

22479

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.514

Gnomad AMR

AF:

0.657

Gnomad ASJ

AF:

0.501

Gnomad EAS

AF:

0.825

Gnomad SAS

AF:

0.583

Gnomad FIN

AF:

0.660

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.576

Gnomad OTH

AF:

0.532

GnomAD4 exome

AF:

0.578

AC:

809900

AN:

1400386

Hom.:

238240

Cov.:

AF XY:

0.578

AC XY:

399434

AN XY:

691152

show subpopulations

African (AFR)

AF:

0.293

AC:

9322

AN:

31824

American (AMR)

AF:

0.740

AC:

27419

AN:

37030

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

12440

AN:

24642

East Asian (EAS)

AF:

0.862

AC:

31113

AN:

36110

South Asian (SAS)

AF:

0.567

AC:

45536

AN:

80308

European-Finnish (FIN)

AF:

0.648

AC:

31061

AN:

47940

Middle Eastern (MID)

AF:

0.486

AC:

2478

AN:

5102

European-Non Finnish (NFE)

AF:

0.572

AC:

617217

AN:

1079460

Other (OTH)

AF:

0.575

AC:

33314

AN:

57970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

16054

32108

48163

64217

80271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.523

AC:

79486

AN:

152094

Hom.:

22501

Cov.:

AF XY:

0.532

AC XY:

39594

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.307

AC:

12715

AN:

41480

American (AMR)

AF:

0.658

AC:

10054

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.501

AC:

1739

AN:

3468

East Asian (EAS)

AF:

0.825

AC:

4265

AN:

5172

South Asian (SAS)

AF:

0.582

AC:

2806

AN:

4822

European-Finnish (FIN)

AF:

0.660

AC:

6991

AN:

10590

Middle Eastern (MID)

AF:

0.493

AC:

144

AN:

292

European-Non Finnish (NFE)

AF:

0.576

AC:

39170

AN:

67964

Other (OTH)

AF:

0.536

AC:

1133

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1800

3599

5399

7198

8998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.562

Hom.:

97398

Bravo

AF:

0.515

Asia WGS

AF:

0.721

AC:

2504

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

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

-0.87

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

0.30

PromoterAI

0.015

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000075

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-127419801-C-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