2-127418286-C-T

Variant names:

• chr2-127418286-C-T
• rs1799808
• NM_000312.4:c.-228C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.96
• Publications: 32 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	c.-228C>T		upstream_gene_variant		ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.-228C>T		upstream_gene_variant		1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50490 AN: 151928 Hom.: 9225 Cov.: 32

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

African (AFR) AF: 0.201 AC: 2082 AN: 10336

American (AMR) AF: 0.646 AC: 16411 AN: 25400

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 3033 AN: 8258

East Asian (EAS) AF: 0.571 AC: 5260 AN: 9208

South Asian (SAS) AF: 0.216 AC: 11618 AN: 53812

European-Finnish (FIN) AF: 0.395 AC: 4269 AN: 10804

Middle Eastern (MID) AF: 0.297 AC: 833 AN: 2802

European-Non Finnish (NFE) AF: 0.362 AC: 90640 AN: 250598

Other (OTH) AF: 0.370 AC: 6051 AN: 16364

GnomAD4 genome AF: 0.332 AC: 50513 AN: 152048 Hom.: 9235 Cov.: 32 AF XY: 0.337 AC XY: 25068 AN XY: 74320

African (AFR) AF: 0.203 AC: 8429 AN: 41498

American (AMR) AF: 0.495 AC: 7558 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3468

East Asian (EAS) AF: 0.569 AC: 2928 AN: 5150

South Asian (SAS) AF: 0.223 AC: 1074 AN: 4820

European-Finnish (FIN) AF: 0.398 AC: 4202 AN: 10554

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23944 AN: 67966

Other (OTH) AF: 0.335 AC: 708 AN: 2114

Alfa AF: 0.351 Hom.: 26027

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

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
PhyloP100		-3.0
PromoterAI		-0.0069	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1799808; hg19: chr2-128175862; COSMIC: COSV107237731;