Genetic Variant PROC:c.-228C>T (chr2-127418286-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000312.4(PROC):c.-228C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 539,630 control chromosomes in the GnomAD database, including 37,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9235 hom., cov: 32)

Exomes 𝑓: 0.36 ( 27822 hom. )

Consequence

PROC
NM_000312.4 upstream_gene

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.96

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 2-127418286-C-T is Benign according to our data. Variant chr2-127418286-C-T is described in ClinVar as [Benign]. Clinvar id is 1164169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4 link	c.-228C>T		upstream_gene_variant		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.-228C>T		upstream_gene_variant		1	NM_000312.4	ENSP00000234071.4		P04070-1

Frequencies

GnomAD3 genomes

AF:

0.332

AC:

50490

AN:

151928

Hom.:

9225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.203

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.568

Gnomad SAS

AF:

0.224

Gnomad FIN

AF:

0.398

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.352

Gnomad OTH

AF:

0.339

GnomAD4 exome

AF:

0.362

AC:

140197

AN:

387582

Hom.:

27822

AF XY:

0.348

AC XY:

70556

AN XY:

202560

show subpopulations

Gnomad4 AFR exome

AF:

0.201

Gnomad4 AMR exome

AF:

0.646

Gnomad4 ASJ exome

AF:

0.367

Gnomad4 EAS exome

AF:

0.571

Gnomad4 SAS exome

AF:

0.216

Gnomad4 FIN exome

AF:

0.395

Gnomad4 NFE exome

AF:

0.362

Gnomad4 OTH exome

AF:

0.370

GnomAD4 genome

AF:

0.332

AC:

50513

AN:

152048

Hom.:

9235

Cov.:

AF XY:

0.337

AC XY:

25068

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.203

Gnomad4 AMR

AF:

0.495

Gnomad4 ASJ

AF:

0.341

Gnomad4 EAS

AF:

0.569

Gnomad4 SAS

AF:

0.223

Gnomad4 FIN

AF:

0.398

Gnomad4 NFE

AF:

0.352

Gnomad4 OTH

AF:

0.335

Alfa

AF:

0.356

Hom.:

9942

Bravo

AF:

0.340

Asia WGS

AF:

0.395

AC:

1371

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.40

DANN

Benign

0.72

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over