chr2-127419972-C-T

Variant names:

• chr2-127419972-C-T
• rs148490199
• NM_000312.4:c.30C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001375607.1(PROC):​c.149C>T​(p.Ser50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,613,872 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S50S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: PROC NM_001375607.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.220
• 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):

• 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.

• 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=-0.77).
• BP6: Variant 2-127419972-C-T is Benign according to our data. Variant chr2-127419972-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469121.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000584 (89/152318) while in subpopulation AMR AF = 0.00431 (66/15304). AF 95% confidence interval is 0.00348. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.30C>T	p.Phe10Phe	synonymous	Exon 2 of 9	NP_000303.1	P04070-1
	PROC	NM_001375607.1		c.149C>T	p.Ser50Leu	missense	Exon 2 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.213C>T	p.Phe71Phe	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.30C>T	p.Phe10Phe	synonymous	Exon 2 of 9	ENSP00000234071.4	P04070-1
	PROC	ENST00000883860.1		c.30C>T	p.Phe10Phe	synonymous	Exon 2 of 8	ENSP00000553919.1
	PROC	ENST00000883897.1		c.30C>T	p.Phe10Phe	synonymous	Exon 1 of 7	ENSP00000553956.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000923 AC: 232 AN: 251336 AF XY: 0.000736

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000219 AC: 320 AN: 1461554 Hom.: 3 Cov.: 34 AF XY: 0.000186 AC XY: 135 AN XY: 727086

African (AFR) AF: 0.000209 AC: 7 AN: 33466

American (AMR) AF: 0.00626 AC: 280 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111998

Other (OTH) AF: 0.000215 AC: 13 AN: 60360

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74478

African (AFR) AF: 0.000505 AC: 21 AN: 41576

American (AMR) AF: 0.00431 AC: 66 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000937

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.2
DANN	Benign	0.61
PhyloP100		-0.22
PromoterAI		-0.054	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs148490199; hg19: chr2-128177548; COSMIC: COSV52166715; COSMIC: COSV52166715;