Genetic Variant F2:c.80-13dupC (chr11-46719682-A-AC) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000506.5(F2):c.80-13dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000343 in 1,575,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

F2
NM_000506.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.62

Publications

0 publications found

Variant links:

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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
congenital prothrombin deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

F2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 11-46719682-A-AC is Benign according to our data. Variant chr11-46719682-A-AC is described in ClinVar as Benign. ClinVar VariationId is 2870553.Status of the report is criteria_provided_single_submitter, 1 stars.

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.80-13dupC		intron	N/A	NP_000497.1	P00734

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
F2	ENST00000311907.10	TSL:1 MANE Select	c.80-20_80-19insC	intron	N/A	ENSP00000308541.5	P00734
F2	ENST00000862106.1		c.80-20_80-19insC	intron	N/A	ENSP00000532165.1
F2	ENST00000862118.1		c.80-20_80-19insC	intron	N/A	ENSP00000532177.1

Frequencies

GnomAD3 genomes

AF:

0.0000332

AC:

AN:

150706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000962

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000103

AC:

AN:

194730

AF XY:

0.0000672

show subpopulations

Gnomad AFR exome

AF:

0.0000834

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000804

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000725

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000344

AC:

AN:

1425048

Hom.:

Cov.:

AF XY:

0.0000354

AC XY:

AN XY:

705368

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32650

American (AMR)

AF:

0.0000250

AC:

AN:

39926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25364

East Asian (EAS)

AF:

0.000290

AC:

AN:

37942

South Asian (SAS)

AF:

0.0000743

AC:

AN:

80808

European-Finnish (FIN)

AF:

0.0000594

AC:

AN:

50518

Middle Eastern (MID)

AF:

0.000235

AC:

AN:

4254

European-Non Finnish (NFE)

AF:

0.0000201

AC:

AN:

1094580

Other (OTH)

AF:

0.0000678

AC:

AN:

59006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000332

AC:

AN:

150820

Hom.:

Cov.:

AF XY:

0.0000543

AC XY:

AN XY:

73598

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41044

American (AMR)

AF:

0.00

AC:

AN:

15140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000195

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4698

European-Finnish (FIN)

AF:

0.0000962

AC:

AN:

10396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67670

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital prothrombin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

BranchPoint Hunter

4.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over