2-127420802-G-A

Variant names:

• chr2-127420802-G-A
• rs2069915
• NM_000312.4:c.71-481G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000312.4(PROC):​c.71-481G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 152,018 control chromosomes in the GnomAD database, including 11,363 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (11363 hom., cov: 32)
• Consequence: PROC NM_000312.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.491
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.71-481G>A		intron_variant	Intron 2 of 8	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.71-481G>A		intron_variant	Intron 2 of 8	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56407 AN: 151900 Hom.: 11354 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.378

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.371 AC: 56435 AN: 152018 Hom.: 11363 Cov.: 32 AF XY: 0.374 AC XY: 27805 AN XY: 74270

African (AFR) AF: 0.229 AC: 9486 AN: 41482

American (AMR) AF: 0.530 AC: 8094 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1601 AN: 3470

East Asian (EAS) AF: 0.564 AC: 2895 AN: 5130

South Asian (SAS) AF: 0.237 AC: 1143 AN: 4818

European-Finnish (FIN) AF: 0.423 AC: 4471 AN: 10558

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27449 AN: 67968

Other (OTH) AF: 0.373 AC: 787 AN: 2112

Alfa AF: 0.276 Hom.: 761

Bravo AF: 0.379

Asia WGS AF: 0.405 AC: 1407 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.6
DANN	Benign	0.80
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2069915; hg19: chr2-128178378;