rs61731660

Variant names:

• chr2-127428667-G-A
• rs61731660
• NM_000312.4:c.1107G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-127428667-G-A
• chr2-127428667-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000312.4(PROC):​c.1107G>A​(p.Pro369Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,613,938 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (41 hom.)
• Consequence: PROC NM_000312.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.29
• 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

LOC105373608 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.011).
• BP6: Variant 2-127428667-G-A is Benign according to our data. Variant chr2-127428667-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1787/152320) while in subpopulation AFR AF = 0.0396 (1648/41580). AF 95% confidence interval is 0.038. There are 37 homozygotes in GnomAd4. There are 833 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 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.1107G>A	p.Pro369Pro	synonymous	Exon 9 of 9	NP_000303.1	P04070-1
	PROC	NM_001375607.1		c.1293G>A	p.Pro431Pro	synonymous	Exon 8 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.1290G>A	p.Pro430Pro	synonymous	Exon 9 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.1107G>A	p.Pro369Pro	synonymous	Exon 9 of 9	ENSP00000234071.4	P04070-1
	PROC	ENST00000883860.1		c.1281G>A	p.Pro427Pro	synonymous	Exon 8 of 8	ENSP00000553919.1
	PROC	ENST00000883897.1		c.1281G>A	p.Pro427Pro	synonymous	Exon 7 of 7	ENSP00000553956.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1784 AN: 152202 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00357 AC: 896 AN: 251292 AF XY: 0.00297

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000915

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00197 AC: 2882 AN: 1461618 Hom.: 41 Cov.: 31 AF XY: 0.00181 AC XY: 1317 AN XY: 727130

African (AFR) AF: 0.0440 AC: 1472 AN: 33480

American (AMR) AF: 0.00195 AC: 87 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

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

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53146

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000885 AC: 984 AN: 1112012

Other (OTH) AF: 0.00329 AC: 199 AN: 60396

GnomAD4 genome AF: 0.0117 AC: 1787 AN: 152320 Hom.: 37 Cov.: 33 AF XY: 0.0112 AC XY: 833 AN XY: 74492

African (AFR) AF: 0.0396 AC: 1648 AN: 41580

American (AMR) AF: 0.00373 AC: 57 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68014

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00686 Hom.: 9

Bravo AF: 0.0135

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00172

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)
-	-	1	Thrombophilia due to protein C deficiency, autosomal dominant;C2676759:Thrombophilia due to protein C deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.13
DANN	Benign	0.65
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs61731660; hg19: chr2-128186243;