11-46719248-C-G

Variant names:

• chr11-46719248-C-G
• rs775021214
• NM_000506.5:c.13C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000506.5(F2):​c.13C>G​(p.Arg5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: F2 NM_000506.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.653
• Publications: 2 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• 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 congenital prothrombin deficiency, thrombophilia due to thrombin defect.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0948233).

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.13C>G	p.Arg5Gly	missense	Exon 1 of 14	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.13C>G	p.Arg5Gly	missense	Exon 1 of 14	ENSP00000308541.5	P00734
	F2	ENST00000862106.1		c.13C>G	p.Arg5Gly	missense	Exon 1 of 15	ENSP00000532165.1
	F2	ENST00000862118.1		c.13C>G	p.Arg5Gly	missense	Exon 1 of 14	ENSP00000532177.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 248980 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461468 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727032

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.65
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift4G	Benign	0.10	T
Polyphen		0.0080	B
Vest4		0.25
MutPred		0.54		Loss of methylation at V5 (P = 0.0366)
MVP		0.71
MPC		0.75
ClinPred		0.058	T
GERP RS		2.8
PromoterAI		-0.019	Neutral
Varity_R		0.31
gMVP		0.92
Mutation Taster		=78/22	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: rs775021214; hg19: chr11-46740798; COSMIC: COSV100319556; COSMIC: COSV100319556;