rs2070851

Variant names:

• chr11-46722978-T-C
• rs2070851
• NM_000506.5:c.317-202T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000506.5(F2):​c.317-202T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 670,508 control chromosomes in the GnomAD database, including 25,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4292 hom., cov: 32)
  • Exomes 𝑓: 0.26 (21093 hom.)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.840
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-46722978-T-C is Benign according to our data. Variant chr11-46722978-T-C is described in ClinVar as Benign. ClinVar VariationId is 1183393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5	c.317-202T>C		intron_variant	Intron 4 of 13	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.317-202T>C		intron_variant	Intron 4 of 13	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.317-202T>C		intron_variant	Intron 4 of 13	5		ENSP00000433907.1
F2	ENST00000442468.1	c.287-202T>C		intron_variant	Intron 4 of 7	3		ENSP00000387413.1
F2	ENST00000490274.1	n.-202T>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32244 AN: 152052 Hom.: 4284 Cov.: 32

Gnomad AFR AF: 0.0826

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.260 AC: 135018 AN: 518338 Hom.: 21093 AF XY: 0.260 AC XY: 72546 AN XY: 279306

African (AFR) AF: 0.0758 AC: 1168 AN: 15412

American (AMR) AF: 0.402 AC: 13340 AN: 33176

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 2969 AN: 17592

East Asian (EAS) AF: 0.609 AC: 19104 AN: 31348

South Asian (SAS) AF: 0.275 AC: 15644 AN: 56896

European-Finnish (FIN) AF: 0.297 AC: 9541 AN: 32100

Middle Eastern (MID) AF: 0.220 AC: 528 AN: 2398

European-Non Finnish (NFE) AF: 0.220 AC: 66102 AN: 300462

Other (OTH) AF: 0.229 AC: 6622 AN: 28954

GnomAD4 genome AF: 0.212 AC: 32253 AN: 152170 Hom.: 4292 Cov.: 32 AF XY: 0.221 AC XY: 16430 AN XY: 74380

African (AFR) AF: 0.0824 AC: 3424 AN: 41554

American (AMR) AF: 0.287 AC: 4385 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 595 AN: 3464

East Asian (EAS) AF: 0.593 AC: 3059 AN: 5162

South Asian (SAS) AF: 0.275 AC: 1327 AN: 4818

European-Finnish (FIN) AF: 0.322 AC: 3413 AN: 10588

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15351 AN: 67992

Other (OTH) AF: 0.193 AC: 408 AN: 2112

Alfa AF: 0.229 Hom.: 1182

Bravo AF: 0.207

Asia WGS AF: 0.338 AC: 1174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.76
PhyloP100		-0.84
Mutation Taster		=100/0	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: rs2070851; hg19: chr11-46744528;