2-127418463-G-A

Variant names:

• chr2-127418463-G-A
• rs536613560
• NM_000312.4:c.-51G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000312.4(PROC):​c.-51G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,289,776 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: PROC NM_000312.4 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0670
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.096).
• BP6: Variant 2-127418463-G-A is Benign according to our data. Variant chr2-127418463-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3037389.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000224 (255/1137506) while in subpopulation SAS AF = 0.00269 (205/76204). AF 95% confidence interval is 0.00239. There are 3 homozygotes in GnomAdExome4. There are 176 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.-51G>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.-51G>A		5_prime_UTR_variant	Exon 1 of 9	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000518 AC: 71 AN: 137024 AF XY: 0.000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000224 AC: 255 AN: 1137506 Hom.: 3 Cov.: 29 AF XY: 0.000315 AC XY: 176 AN XY: 558052

African (AFR) AF: 0.0000410 AC: 1 AN: 24414

American (AMR) AF: 0.00 AC: 0 AN: 28266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15942

East Asian (EAS) AF: 0.00 AC: 0 AN: 12840

South Asian (SAS) AF: 0.00269 AC: 205 AN: 76204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13064

Middle Eastern (MID) AF: 0.000682 AC: 3 AN: 4402

European-Non Finnish (NFE) AF: 0.0000391 AC: 36 AN: 920840

Other (OTH) AF: 0.000241 AC: 10 AN: 41534

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74442

African (AFR) AF: 0.0000241 AC: 1 AN: 41530

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000718

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PROC-related disorder Benign:1

May 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	18
DANN	Benign	0.97
PhyloP100		-0.067
PromoterAI		-0.077	Neutral
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs536613560; hg19: chr2-128176039; COSMIC: COSV99300769; COSMIC: COSV99300769;