rs144300387

Variant names:

• chr2-127420008-T-C
• rs144300387
• NM_000312.4:c.66T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001375607.1(PROC):​c.185T>C​(p.Leu62Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000625 in 1,613,240 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (15 hom.)
• Consequence: PROC NM_001375607.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.31
• Publications: 3 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 -17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_001375607.1
• 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: 1.2829 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein C deficiency.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-127420008-T-C is Benign according to our data. Variant chr2-127420008-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00127 (193/152220) while in subpopulation EAS AF = 0.0273 (141/5166). AF 95% confidence interval is 0.0236. There are 7 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375607.1. 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.66T>C	p.Pro22Pro	synonymous	Exon 2 of 9	NP_000303.1	P04070-1
	PROC	NM_001375607.1		c.185T>C	p.Leu62Pro	missense	Exon 2 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.249T>C	p.Pro83Pro	synonymous	Exon 2 of 9	NP_001362531.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	ENST00000234071.8	TSL:1 MANE Select	c.66T>C	p.Pro22Pro	synonymous	Exon 2 of 9	ENSP00000234071.4	P04070-1
	PROC	ENST00000883860.1		c.66T>C	p.Pro22Pro	synonymous	Exon 2 of 8	ENSP00000553919.1
	PROC	ENST00000883897.1		c.66T>C	p.Pro22Pro	synonymous	Exon 1 of 7	ENSP00000553956.1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152102 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0274

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00213 AC: 536 AN: 251228 AF XY: 0.00194

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000559 AC: 816 AN: 1461020 Hom.: 15 Cov.: 34 AF XY: 0.000532 AC XY: 387 AN XY: 726820

African (AFR) AF: 0.000299 AC: 10 AN: 33456

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0134 AC: 532 AN: 39700

South Asian (SAS) AF: 0.000986 AC: 85 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5184

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111960

Other (OTH) AF: 0.00282 AC: 170 AN: 60304

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152220 Hom.: 7 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74422

African (AFR) AF: 0.000698 AC: 29 AN: 41536

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0273 AC: 141 AN: 5166

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000364 Hom.: 1

Bravo AF: 0.000933

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Thrombophilia due to protein C deficiency, autosomal dominant (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.59
PhyloP100		1.3
PromoterAI		-0.082	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs144300387; hg19: chr2-128177584;