rs200045749

Variant names:

• chr2-127423170-C-T
• rs200045749
• NM_000312.4:c.399C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 3P and 18B. PM1 PP2 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001375606.1(PROC):​c.554C>T​(p.Ala185Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,494,778 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A185A) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 34)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: PROC NM_001375606.1 missense
• Scores: Splicing: ADA: 0.0009557
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.461
• Publications: 2 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 -15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_001375606.1
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.88339 (below the threshold of 3.09). Trascript score misZ: 1.5107 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary thrombophilia due to congenital protein C deficiency, thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive.
• BP4: Computational evidence support a benign effect (REVEL=0.03).
• BP6: Variant 2-127423170-C-T is Benign according to our data. Variant chr2-127423170-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00389 (576/147938) while in subpopulation AFR AF = 0.0135 (552/40912). AF 95% confidence interval is 0.0126. There are 4 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 SD,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375606.1. 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.399C>T	p.Arg133Arg	splice_region synonymous	Exon 5 of 9	NP_000303.1	P04070-1
	PROC	NM_001375606.1		c.554C>T	p.Ala185Val	missense	Exon 4 of 8	NP_001362535.1	B4DPQ3
	PROC	NM_001375607.1		c.483C>T	p.Arg161Arg	synonymous	Exon 5 of 8	NP_001362536.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	ENST00000234071.8	TSL:1 MANE Select	c.399C>T	p.Arg133Arg	splice_region synonymous	Exon 5 of 9	ENSP00000234071.4	P04070-1
	PROC	ENST00000883860.1		c.471C>T	p.Arg157Arg	synonymous	Exon 5 of 8	ENSP00000553919.1
	PROC	ENST00000883897.1		c.471C>T	p.Arg157Arg	synonymous	Exon 4 of 7	ENSP00000553956.1

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 574 AN: 147822 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000300

Gnomad OTH AF: 0.00195

GnomAD2 exomes AF: 0.000882 AC: 163 AN: 184728 AF XY: 0.000702

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.000476

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.000406 AC: 547 AN: 1346840 Hom.: 4 Cov.: 36 AF XY: 0.000309 AC XY: 206 AN XY: 666068

African (AFR) AF: 0.0156 AC: 466 AN: 29928

American (AMR) AF: 0.000645 AC: 25 AN: 38764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22236

East Asian (EAS) AF: 0.00 AC: 0 AN: 30952

South Asian (SAS) AF: 0.0000492 AC: 4 AN: 81332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41162

Middle Eastern (MID) AF: 0.000409 AC: 2 AN: 4890

European-Non Finnish (NFE) AF: 0.00000670 AC: 7 AN: 1044124

Other (OTH) AF: 0.000804 AC: 43 AN: 53452

GnomAD4 genome AF: 0.00389 AC: 576 AN: 147938 Hom.: 4 Cov.: 34 AF XY: 0.00374 AC XY: 270 AN XY: 72250

African (AFR) AF: 0.0135 AC: 552 AN: 40912

American (AMR) AF: 0.00113 AC: 17 AN: 14998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 4720

South Asian (SAS) AF: 0.00 AC: 0 AN: 4484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9608

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0000300 AC: 2 AN: 66594

Other (OTH) AF: 0.00193 AC: 4 AN: 2070

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00457

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Thrombophilia due to protein C deficiency, autosomal dominant (3)
-	-	1	PROC-related disorder (1)
-	-	1	Reduced protein C activity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		-0.46
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00096
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.090		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: rs200045749; hg19: chr2-128180746;