2-127418464-A-T

Variant names:

• chr2-127418464-A-T
• rs1799810
• NM_000312.4:c.-50A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001375607.1(PROC):​c.18A>T​(p.Arg6Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,289,384 control chromosomes in the GnomAD database, including 118,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15374 hom., cov: 32)
  • Exomes 𝑓: 0.42 (103340 hom.)
• Consequence: PROC NM_001375607.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 1.21
• Publications: 54 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):

• hereditary thrombophilia due to congenital protein C deficiency

  Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• thrombophilia due to protein C deficiency, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-127418464-A-T is Benign according to our data. Variant chr2-127418464-A-T is described in ClinVar as Benign. ClinVar VariationId is 255808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

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.-50A>T		5_prime_UTR	Exon 1 of 9	NP_000303.1
	PROC	NM_001375607.1		c.18A>T	p.Arg6Arg	synonymous	Exon 1 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.18A>T	p.Arg6Arg	synonymous	Exon 1 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.-50A>T		5_prime_UTR	Exon 1 of 9	ENSP00000234071.4
	PROC	ENST00000883860.1		c.-50A>T		5_prime_UTR	Exon 1 of 8	ENSP00000553919.1
	PROC	ENST00000883843.1		c.-50A>T		5_prime_UTR	Exon 1 of 8	ENSP00000553902.1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66581 AN: 151930 Hom.: 15366 Cov.: 32

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.436

GnomAD2 exomes AF: 0.381 AC: 52160 AN: 137010 AF XY: 0.389

Gnomad AFR exome AF: 0.564

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.176

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.423 AC: 481127 AN: 1137336 Hom.: 103340 Cov.: 43 AF XY: 0.424 AC XY: 236561 AN XY: 557988

African (AFR) AF: 0.563 AC: 13745 AN: 24412

American (AMR) AF: 0.243 AC: 6862 AN: 28266

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 7887 AN: 15940

East Asian (EAS) AF: 0.168 AC: 2151 AN: 12840

South Asian (SAS) AF: 0.436 AC: 33233 AN: 76198

European-Finnish (FIN) AF: 0.358 AC: 4676 AN: 13062

Middle Eastern (MID) AF: 0.493 AC: 2169 AN: 4402

European-Non Finnish (NFE) AF: 0.427 AC: 393110 AN: 920686

Other (OTH) AF: 0.416 AC: 17294 AN: 41530

GnomAD4 genome AF: 0.438 AC: 66613 AN: 152048 Hom.: 15374 Cov.: 32 AF XY: 0.429 AC XY: 31886 AN XY: 74328

African (AFR) AF: 0.561 AC: 23250 AN: 41442

American (AMR) AF: 0.322 AC: 4929 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1727 AN: 3472

East Asian (EAS) AF: 0.174 AC: 898 AN: 5168

South Asian (SAS) AF: 0.420 AC: 2023 AN: 4818

European-Finnish (FIN) AF: 0.341 AC: 3604 AN: 10582

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28687 AN: 67962

Other (OTH) AF: 0.432 AC: 912 AN: 2112

Alfa AF: 0.439 Hom.: 2728

Bravo AF: 0.440

Asia WGS AF: 0.272 AC: 951 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	not provided (2)
-	-	2	Thrombophilia due to protein C deficiency, autosomal dominant (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		1.2
PromoterAI		-0.060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs1799810; hg19: chr2-128176040; COSMIC: COSV52166678; COSMIC: COSV52166678;