11-46739326-GG-AA

Variant names:

• chr11-46739326-GG-AA
• NM_000506.5:c.1787_1788delGGinsAA
• F2 p.Arg596Gln

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1_Very_Strong PM1 PM5 PP2

The NM_000506.5(F2):​c.1787_1788delGGinsAA​(p.Arg596Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R596L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: F2 NM_000506.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.88
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• congenital prothrombin deficiency

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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS1: Transcript NM_000506.5 (F2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000506.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-46739326-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 31922.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.1083 (below the threshold of 3.09). Trascript score misZ: 2.7629 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to thrombin defect, congenital prothrombin deficiency.

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.1787_1788delGGinsAA	p.Arg596Gln	missense	N/A	NP_000497.1	P00734

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	ENST00000311907.10	TSL:1 MANE Select	c.1787_1788delGGinsAA	p.Arg596Gln	missense	N/A	ENSP00000308541.5	P00734
	F2	ENST00000862106.1		c.1883_1884delGGinsAA	p.Arg628Gln	missense	N/A	ENSP00000532165.1
	F2	ENST00000862118.1		c.1835_1836delGGinsAA	p.Arg612Gln	missense	N/A	ENSP00000532177.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-46760876;