NM_000506.5:c.1824C>T

Variant names:

• chr11-46739363-C-T
• rs3136532
• NM_000506.5:c.1824C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000506.5(F2):​c.1824C>T​(p.Arg608Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00614 in 1,614,056 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (37 hom.)
• Consequence: F2 NM_000506.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.469
• Publications: 7 publications found

Genes affected

F2 (HGNC:3535): (coagulation factor II, thrombin) This gene encodes the prothrombin protein (also known as coagulation factor II). This protein is proteolytically cleaved in multiple steps to form the activated serine protease thrombin. The activated thrombin enzyme plays an important role in thrombosis and hemostasis by converting fibrinogen to fibrin during blood clot formation, by stimulating platelet aggregation, and by activating additional coagulation factors. Thrombin also plays a role in cell proliferation, tissue repair, and angiogenesis as well as maintaining vascular integrity during development and postnatal life. Peptides derived from the C-terminus of this protein have antimicrobial activity against E. coli and P. aeruginosa. Mutations in this gene lead to various forms of thrombosis and dysprothrombinemia. Rapid increases in cytokine levels following coronavirus infections can dysregulate the coagulation cascade and produce thrombosis, compromised blood supply, and organ failure. [provided by RefSeq, May 2020]

F2 Gene-Disease associations (from GenCC):

• thrombophilia due to thrombin defect

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• congenital prothrombin deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-46739363-C-T is Benign according to our data. Variant chr11-46739363-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256314.
• BP7: Synonymous conserved (PhyloP=0.469 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00466 (709/152172) while in subpopulation NFE AF = 0.00713 (485/68014). AF 95% confidence interval is 0.00661. There are 3 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000506.5. 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
	F2	NM_000506.5	MANE Select	c.1824C>T	p.Arg608Arg	synonymous	Exon 14 of 14	NP_000497.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	ENST00000311907.10	TSL:1 MANE Select	c.1824C>T	p.Arg608Arg	synonymous	Exon 14 of 14	ENSP00000308541.5
	F2	ENST00000862106.1		c.1920C>T	p.Arg640Arg	synonymous	Exon 15 of 15	ENSP00000532165.1
	F2	ENST00000862118.1		c.1872C>T	p.Arg624Arg	synonymous	Exon 14 of 14	ENSP00000532177.1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 709 AN: 152054 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00811

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00713

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00480 AC: 1208 AN: 251466 AF XY: 0.00500

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00882

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00629 AC: 9201 AN: 1461884 Hom.: 37 Cov.: 33 AF XY: 0.00615 AC XY: 4473 AN XY: 727242

African (AFR) AF: 0.000777 AC: 26 AN: 33478

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

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

South Asian (SAS) AF: 0.00341 AC: 294 AN: 86258

European-Finnish (FIN) AF: 0.00919 AC: 491 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.00716 AC: 7961 AN: 1112008

Other (OTH) AF: 0.00561 AC: 339 AN: 60394

GnomAD4 genome AF: 0.00466 AC: 709 AN: 152172 Hom.: 3 Cov.: 32 AF XY: 0.00472 AC XY: 351 AN XY: 74390

African (AFR) AF: 0.00111 AC: 46 AN: 41492

American (AMR) AF: 0.00249 AC: 38 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4822

European-Finnish (FIN) AF: 0.00811 AC: 86 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00713 AC: 485 AN: 68014

Other (OTH) AF: 0.00617 AC: 13 AN: 2106

Alfa AF: 0.00599 Hom.: 6

Bravo AF: 0.00367

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00575

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital prothrombin deficiency (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.0
DANN	Benign	0.81
PhyloP100		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs3136532; hg19: chr11-46760913;