chr2-127426114-C-T

Variant names:

• chr2-127426114-C-T
• rs146922325
• NM_000312.4:c.565C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1 PP2 PP5 BP4 BS1_Supporting BS2

The NM_000312.4(PROC):​c.565C>T​(p.Arg189Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,004 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:3
• Conservation: PhyloP100: -0.0360
• Publications: 36 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

LOC105373608 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000312.4
• 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: 1.6095 (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.
• PP5: Variant 2-127426114-C-T is Pathogenic according to our data. Variant chr2-127426114-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161342.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0060937107). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00046 (70/152212) while in subpopulation EAS AF = 0.00888 (46/5180). AF 95% confidence interval is 0.00684. There are 1 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,SD gene

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.565C>T	p.Arg189Trp	missense	Exon 7 of 9	NP_000303.1	P04070-1
	PROC	NM_001375607.1		c.751C>T	p.Arg251Trp	missense	Exon 6 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.748C>T	p.Arg250Trp	missense	Exon 7 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.565C>T	p.Arg189Trp	missense	Exon 7 of 9	ENSP00000234071.4	P04070-1
	PROC	ENST00000883860.1		c.739C>T	p.Arg247Trp	missense	Exon 6 of 8	ENSP00000553919.1
	PROC	ENST00000883897.1		c.739C>T	p.Arg247Trp	missense	Exon 5 of 7	ENSP00000553956.1

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152094 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000752 AC: 189 AN: 251346 AF XY: 0.000751

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00805

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461792 Hom.: 2 Cov.: 31 AF XY: 0.000220 AC XY: 160 AN XY: 727190

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00390 AC: 155 AN: 39698

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112000

Other (OTH) AF: 0.000894 AC: 54 AN: 60392

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74414

African (AFR) AF: 0.000193 AC: 8 AN: 41518

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00888 AC: 46 AN: 5180

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000198 Hom.: 1

Bravo AF: 0.000264

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	3	-	Thrombophilia due to protein C deficiency, autosomal dominant (6)
1	-	-	Reduced protein C activity (1)
1	-	-	Thrombophilia 3 due to protein C deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0061	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L
PhyloP100		-0.036
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.58
Sift	Benign	0.10	T
Sift4G	Benign	0.064	T
Polyphen		0.18	B
Vest4		0.12
MVP		0.91
MPC		0.47
ClinPred		0.0091	T
GERP RS		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.81
Mutation Taster		=29/71	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs146922325; hg19: chr2-128183690; COSMIC: COSV52167078; COSMIC: COSV52167078;