rs2069920

Variant names:

• chr2-127422070-T-C
• rs2069920
• NM_000312.4:c.237+621T>C

Variant summary

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

The NM_000312.4(PROC):​c.237+621T>C 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 152,008 control chromosomes in the GnomAD database, including 11,366 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 (11366 hom., cov: 33)
• Consequence: PROC NM_000312.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.277
• Publications: 8 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	NM_000312.4	MANE Select	c.237+621T>C		intron	N/A	NP_000303.1	P04070-1
	PROC	NM_001375607.1		c.321+621T>C		intron	N/A	NP_001362536.1
	PROC	NM_001375602.1		c.420+621T>C		intron	N/A	NP_001362531.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	ENST00000234071.8	TSL:1 MANE Select	c.237+621T>C		intron	N/A	ENSP00000234071.4	P04070-1
	PROC	ENST00000883860.1		c.309+549T>C		intron	N/A	ENSP00000553919.1
	PROC	ENST00000883897.1		c.309+549T>C		intron	N/A	ENSP00000553956.1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56304 AN: 151890 Hom.: 11358 Cov.: 33

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.405

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: 56323 AN: 152008 Hom.: 11366 Cov.: 33 AF XY: 0.374 AC XY: 27767 AN XY: 74282

African (AFR) AF: 0.223 AC: 9225 AN: 41452

American (AMR) AF: 0.533 AC: 8147 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1600 AN: 3468

East Asian (EAS) AF: 0.569 AC: 2926 AN: 5144

South Asian (SAS) AF: 0.240 AC: 1157 AN: 4822

European-Finnish (FIN) AF: 0.424 AC: 4477 AN: 10568

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27488 AN: 67948

Other (OTH) AF: 0.373 AC: 788 AN: 2112

Alfa AF: 0.384 Hom.: 1830

Bravo AF: 0.378

Asia WGS AF: 0.406 AC: 1411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.1
DANN	Benign	0.55
PhyloP100		-0.28
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: rs2069920; hg19: chr2-128179646;