Genetic Variant NM_000312.4:c.768T>C (chr2-127427194-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000312.4(PROC):c.768T>C(p.Asp256Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,612,832 control chromosomes in the GnomAD database, including 81,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7054 hom., cov: 33)

Exomes 𝑓: 0.31 ( 74014 hom. )

Consequence

PROC
NM_000312.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: -1.57

Publications

25 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:

LOC105373608 (HGNC:):

LOC105373608 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-127427194-T-C is Benign according to our data. Variant chr2-127427194-T-C is described in ClinVar as Benign. ClinVar VariationId is 255810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.57 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000312.4. 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.768T>C	p.Asp256Asp	synonymous	Exon 8 of 9	NP_000303.1	P04070-1
PROC	NM_001375607.1		c.954T>C	p.Asp318Asp	synonymous	Exon 7 of 8	NP_001362536.1
PROC	NM_001375602.1		c.951T>C	p.Asp317Asp	synonymous	Exon 8 of 9	NP_001362531.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PROC	ENST00000234071.8	TSL:1 MANE Select	c.768T>C	p.Asp256Asp	synonymous	Exon 8 of 9	ENSP00000234071.4	P04070-1
PROC	ENST00000883860.1		c.942T>C	p.Asp314Asp	synonymous	Exon 7 of 8	ENSP00000553919.1
PROC	ENST00000883897.1		c.942T>C	p.Asp314Asp	synonymous	Exon 6 of 7	ENSP00000553956.1

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45331

AN:

151956

Hom.:

7058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.323

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.280

Gnomad FIN

AF:

0.285

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.299

GnomAD2 exomes

AF:

0.272

AC:

67954

AN:

249518

AF XY:

0.278

show subpopulations

Gnomad AFR exome

AF:

0.324

Gnomad AMR exome

AF:

0.170

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.00202

Gnomad FIN exome

AF:

0.286

Gnomad NFE exome

AF:

0.327

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.312

AC:

455241

AN:

1460758

Hom.:

74014

Cov.:

AF XY:

0.312

AC XY:

226373

AN XY:

726682

show subpopulations

African (AFR)

AF:

0.324

AC:

10857

AN:

33476

American (AMR)

AF:

0.176

AC:

7887

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

9102

AN:

26126

East Asian (EAS)

AF:

0.00154

AC:

AN:

39700

South Asian (SAS)

AF:

0.292

AC:

25166

AN:

86246

European-Finnish (FIN)

AF:

0.295

AC:

15535

AN:

52732

Middle Eastern (MID)

AF:

0.355

AC:

2033

AN:

5726

European-Non Finnish (NFE)

AF:

0.330

AC:

366487

AN:

1111670

Other (OTH)

AF:

0.300

AC:

18113

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

16333

32666

49000

65333

81666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11758

23516

35274

47032

58790

<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:

0.298

AC:

45340

AN:

152074

Hom.:

7054

Cov.:

AF XY:

0.291

AC XY:

21662

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.322

AC:

13368

AN:

41490

American (AMR)

AF:

0.231

AC:

3532

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

1191

AN:

3470

East Asian (EAS)

AF:

0.00425

AC:

AN:

5174

South Asian (SAS)

AF:

0.280

AC:

1351

AN:

4826

European-Finnish (FIN)

AF:

0.285

AC:

3010

AN:

10578

Middle Eastern (MID)

AF:

0.340

AC:

100

AN:

294

European-Non Finnish (NFE)

AF:

0.321

AC:

21822

AN:

67936

Other (OTH)

AF:

0.296

AC:

625

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1636

3273

4909

6546

8182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.308

Hom.:

21030

Bravo

AF:

0.295

Asia WGS

AF:

0.136

AC:

476

AN:

3478

EpiCase

AF:

0.318

EpiControl

AF:

0.321

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Thrombophilia due to protein C deficiency, autosomal dominant (3)

not specified (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.94

(source)

DANN

Benign

0.68

PhyloP100

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over