Genetic Variant PROC:c.-21-5C>T (chr2-127419917-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001375607.1(PROC):c.94C>T(p.Leu32Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,613,952 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 4 hom. )

Consequence

PROC
NM_001375607.1 missense

Scores

Splicing: ADA: 0.0009306

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.815

Publications

3 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):

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

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.88339 (below the threshold of 3.09). Trascript score misZ: 1.2829 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein C deficiency.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 2-127419917-C-T is Benign according to our data. Variant chr2-127419917-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 331101.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00183 (279/152336) while in subpopulation SAS AF = 0.00311 (15/4828). AF 95% confidence interval is 0.0025. There are 1 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375607.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PROC	NM_000312.4	MANE Select	c.-21-5C>T		splice_region intron	N/A	NP_000303.1	P04070-1
PROC	NM_001375607.1		c.94C>T	p.Leu32Phe	missense	Exon 2 of 8	NP_001362536.1
PROC	NM_001375602.1		c.158C>T	p.Pro53Leu	missense	Exon 2 of 9	NP_001362531.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PROC	ENST00000234071.8	TSL:1 MANE Select	c.-21-5C>T	splice_region intron	N/A	ENSP00000234071.4	P04070-1
PROC	ENST00000883897.1		c.-26C>T	5_prime_UTR	Exon 1 of 7	ENSP00000553956.1
PROC	ENST00000883902.1		c.-26C>T	5_prime_UTR	Exon 1 of 7	ENSP00000553961.1

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

279

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00282

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00219

AC:

549

AN:

251080

AF XY:

0.00244

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00302

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00286

AC:

4183

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

2072

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33476

American (AMR)

AF:

0.00183

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00256

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00308

AC:

266

AN:

86252

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00319

AC:

3545

AN:

1111978

Other (OTH)

AF:

0.00220

AC:

133

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

265

531

796

1062

1327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00183

AC:

279

AN:

152336

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41586

American (AMR)

AF:

0.00176

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00311

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00282

AC:

192

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00208

Hom.:

Bravo

AF:

0.00172

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00415

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Thrombophilia due to protein C deficiency, autosomal dominant (1)

Thrombophilia due to protein C deficiency, autosomal dominant;C2676759:Thrombophilia due to protein C deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

0.81

PromoterAI

0.0030

Neutral

(source)

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00093

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over