rs62623459

Variant names:

• chr11-46725897-G-A
• rs62623459
• NM_000506.5:c.598G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_000506.5(F2):​c.598G>A​(p.Glu200Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,613,510 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: F2 NM_000506.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:1 U:5 B:3 O:1
• Conservation: PhyloP100: -2.97
• Publications: 11 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: Benign. The variant received -10 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=0.21716785).
• BP6: Variant 11-46725897-G-A is Benign according to our data. Variant chr11-46725897-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 13302.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00131 (200/152248) while in subpopulation NFE AF = 0.00253 (172/68012). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

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.598G>A	p.Glu200Lys	missense	Exon 7 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.598G>A	p.Glu200Lys	missense	Exon 7 of 14	ENSP00000308541.5	P00734
	F2	ENST00000862106.1		c.694G>A	p.Glu232Lys	missense	Exon 8 of 15	ENSP00000532165.1
	F2	ENST00000862118.1		c.598G>A	p.Glu200Lys	missense	Exon 7 of 14	ENSP00000532177.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00110 AC: 275 AN: 250086 AF XY: 0.00101

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00190 AC: 2773 AN: 1461262 Hom.: 5 Cov.: 32 AF XY: 0.00182 AC XY: 1325 AN XY: 726934

African (AFR) AF: 0.000508 AC: 17 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.000509 AC: 27 AN: 52994

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5612

European-Non Finnish (NFE) AF: 0.00237 AC: 2640 AN: 1112004

Other (OTH) AF: 0.00131 AC: 79 AN: 60368

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74444

African (AFR) AF: 0.000433 AC: 18 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.00119

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00125 AC: 152

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Congenital prothrombin deficiency (3)
-	1	1	Thrombophilia due to thrombin defect (2)
-	1	-	Congenital prothrombin deficiency;C0948008:Ischemic stroke;C3160733:Thrombophilia due to thrombin defect;C3280672:Pregnancy loss, recurrent, susceptibility to, 2 (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
1	-	-	PROTHROMBIN TYPE 3 (1)
-	-	-	Cerebral palsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	0.0030
DANN	Benign	0.31
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.39	N
PhyloP100		-3.0
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.26	N
REVEL	Uncertain	0.50
Sift	Benign	0.95	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.43
MVP		0.99
MPC		0.65
ClinPred		0.016	T
GERP RS		-10
Varity_R		0.18
gMVP		0.64
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62623459; hg19: chr11-46747447; COSMIC: COSV105884382;