NM_000506.5:c.240+83C>T

Variant names:

• chr11-46719945-C-T
• rs2070850
• NM_000506.5:c.240+83C>T

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.240+83C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,503,966 control chromosomes in the GnomAD database, including 24,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2402 hom., cov: 32)
  • Exomes 𝑓: 0.16 (22069 hom.)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.148
• Publications: 16 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 11-46719945-C-T is Benign according to our data. Variant chr11-46719945-C-T is described in ClinVar as [Benign]. Clinvar id is 1277924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5	c.240+83C>T		intron_variant	Intron 2 of 13	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.240+83C>T		intron_variant	Intron 2 of 13	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000469189.1	n.363C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2
F2	ENST00000530231.5	c.240+83C>T		intron_variant	Intron 2 of 13	5		ENSP00000433907.1
F2	ENST00000442468.1	c.210+83C>T		intron_variant	Intron 2 of 7	3		ENSP00000387413.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 21993 AN: 152094 Hom.: 2389 Cov.: 32

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.0796

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.158 AC: 214252 AN: 1351754 Hom.: 22069 Cov.: 25 AF XY: 0.159 AC XY: 106417 AN XY: 668400

African (AFR) AF: 0.0387 AC: 1193 AN: 30820

American (AMR) AF: 0.361 AC: 12829 AN: 35558

Ashkenazi Jewish (ASJ) AF: 0.0771 AC: 1920 AN: 24902

East Asian (EAS) AF: 0.571 AC: 20292 AN: 35568

South Asian (SAS) AF: 0.207 AC: 16235 AN: 78322

European-Finnish (FIN) AF: 0.223 AC: 8059 AN: 36080

Middle Eastern (MID) AF: 0.108 AC: 432 AN: 4010

European-Non Finnish (NFE) AF: 0.138 AC: 144501 AN: 1049872

Other (OTH) AF: 0.155 AC: 8791 AN: 56622

GnomAD4 genome AF: 0.145 AC: 22010 AN: 152212 Hom.: 2402 Cov.: 32 AF XY: 0.154 AC XY: 11463 AN XY: 74400

African (AFR) AF: 0.0473 AC: 1967 AN: 41574

American (AMR) AF: 0.237 AC: 3630 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 276 AN: 3466

East Asian (EAS) AF: 0.557 AC: 2877 AN: 5166

South Asian (SAS) AF: 0.208 AC: 1004 AN: 4828

European-Finnish (FIN) AF: 0.249 AC: 2637 AN: 10584

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9244 AN: 67982

Other (OTH) AF: 0.126 AC: 267 AN: 2116

Alfa AF: 0.143 Hom.: 622

Bravo AF: 0.143

Asia WGS AF: 0.304 AC: 1056 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.54
PhyloP100		-0.15
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: rs2070850; hg19: chr11-46741495;