2-127427194-T-C

Variant names:

• chr2-127427194-T-C
• rs5937
• NM_000312.4:c.768T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000312.4(PROC):​c.768T>C​(p.Asp256Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,612,832 control chromosomes in the GnomAD database, including 81,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7054 hom., cov: 33)
  • Exomes 𝑓: 0.31 (74014 hom.)
• Consequence: PROC NM_000312.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: -1.57
• Publications: 25 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-127427194-T-C is Benign according to our data. Variant chr2-127427194-T-C is described in ClinVar as Benign. ClinVar VariationId is 255810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

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.768T>C	p.Asp256Asp	synonymous	Exon 8 of 9	NP_000303.1	P04070-1
	PROC	NM_001375607.1		c.954T>C	p.Asp318Asp	synonymous	Exon 7 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.951T>C	p.Asp317Asp	synonymous	Exon 8 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.768T>C	p.Asp256Asp	synonymous	Exon 8 of 9	ENSP00000234071.4	P04070-1
	PROC	ENST00000883860.1		c.942T>C	p.Asp314Asp	synonymous	Exon 7 of 8	ENSP00000553919.1
	PROC	ENST00000883897.1		c.942T>C	p.Asp314Asp	synonymous	Exon 6 of 7	ENSP00000553956.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45331 AN: 151956 Hom.: 7058 Cov.: 33

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.272 AC: 67954 AN: 249518 AF XY: 0.278

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.00202

Gnomad FIN exome AF: 0.286

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.312 AC: 455241 AN: 1460758 Hom.: 74014 Cov.: 38 AF XY: 0.312 AC XY: 226373 AN XY: 726682

African (AFR) AF: 0.324 AC: 10857 AN: 33476

American (AMR) AF: 0.176 AC: 7887 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 9102 AN: 26126

East Asian (EAS) AF: 0.00154 AC: 61 AN: 39700

South Asian (SAS) AF: 0.292 AC: 25166 AN: 86246

European-Finnish (FIN) AF: 0.295 AC: 15535 AN: 52732

Middle Eastern (MID) AF: 0.355 AC: 2033 AN: 5726

European-Non Finnish (NFE) AF: 0.330 AC: 366487 AN: 1111670

Other (OTH) AF: 0.300 AC: 18113 AN: 60366

GnomAD4 genome AF: 0.298 AC: 45340 AN: 152074 Hom.: 7054 Cov.: 33 AF XY: 0.291 AC XY: 21662 AN XY: 74352

African (AFR) AF: 0.322 AC: 13368 AN: 41490

American (AMR) AF: 0.231 AC: 3532 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1191 AN: 3470

East Asian (EAS) AF: 0.00425 AC: 22 AN: 5174

South Asian (SAS) AF: 0.280 AC: 1351 AN: 4826

European-Finnish (FIN) AF: 0.285 AC: 3010 AN: 10578

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21822 AN: 67936

Other (OTH) AF: 0.296 AC: 625 AN: 2110

Alfa AF: 0.308 Hom.: 21030

Bravo AF: 0.295

Asia WGS AF: 0.136 AC: 476 AN: 3478

EpiCase AF: 0.318

EpiControl AF: 0.321

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	Thrombophilia due to protein C deficiency, autosomal dominant (3)
-	-	1	not specified (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	-0.84
CADD	Benign	0.94
DANN	Benign	0.68
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	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: rs5937; hg19: chr2-128184770; COSMIC: COSV52167368; COSMIC: COSV52167368;