rs2227568

Variant names:

• chr10-73914121-C-T
• rs2227568
• NM_002658.6:c.822C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002658.6(PLAU):​c.822C>T​(p.Asn274Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,432 control chromosomes in the GnomAD database, including 21,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1608 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20183 hom.)
• Consequence: PLAU NM_002658.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.09
• Publications: 19 publications found

Genes affected

PLAU (HGNC:9052): (plasminogen activator, urokinase) This gene encodes a secreted serine protease that converts plasminogen to plasmin. The encoded preproprotein is proteolytically processed to generate A and B polypeptide chains. These chains associate via a single disulfide bond to form the catalytically inactive high molecular weight urokinase-type plasminogen activator (HMW-uPA). HMW-uPA can be further processed into the catalytically active low molecular weight urokinase-type plasminogen activator (LMW-uPA). This low molecular weight form does not bind to the urokinase-type plasminogen activator receptor. Mutations in this gene may be associated with Quebec platelet disorder and late-onset Alzheimer's disease. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

C10orf55 (HGNC:31008): (chromosome 10 putative open reading frame 55) Enables identical protein binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 10-73914121-C-T is Benign according to our data. Variant chr10-73914121-C-T is described in ClinVar as Benign. ClinVar VariationId is 300756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002658.6. 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
	PLAU	NM_002658.6	MANE Select	c.822C>T	p.Asn274Asn	synonymous	Exon 8 of 11	NP_002649.2
	PLAU	NM_001441154.1		c.822C>T	p.Asn274Asn	synonymous	Exon 9 of 12	NP_001428083.1
	PLAU	NM_001441155.1		c.822C>T	p.Asn274Asn	synonymous	Exon 8 of 11	NP_001428084.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAU	ENST00000372764.4	TSL:1 MANE Select	c.822C>T	p.Asn274Asn	synonymous	Exon 8 of 11	ENSP00000361850.3
	C10orf55	ENST00000409178.5	TSL:1	n.269-1046G>A		intron	N/A
	PLAU	ENST00000894723.1		c.822C>T	p.Asn274Asn	synonymous	Exon 7 of 10	ENSP00000564782.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19827 AN: 152132 Hom.: 1609 Cov.: 33

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.0899

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.124

GnomAD2 exomes AF: 0.166 AC: 41745 AN: 250806 AF XY: 0.174

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.0969

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.312

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.159 AC: 232687 AN: 1461182 Hom.: 20183 Cov.: 34 AF XY: 0.163 AC XY: 118366 AN XY: 726930

African (AFR) AF: 0.0612 AC: 2047 AN: 33472

American (AMR) AF: 0.0956 AC: 4273 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 7039 AN: 26124

East Asian (EAS) AF: 0.321 AC: 12736 AN: 39680

South Asian (SAS) AF: 0.240 AC: 20733 AN: 86216

European-Finnish (FIN) AF: 0.152 AC: 8129 AN: 53306

Middle Eastern (MID) AF: 0.174 AC: 1000 AN: 5744

European-Non Finnish (NFE) AF: 0.150 AC: 166738 AN: 1111580

Other (OTH) AF: 0.166 AC: 9992 AN: 60364

GnomAD4 genome AF: 0.130 AC: 19826 AN: 152250 Hom.: 1608 Cov.: 33 AF XY: 0.130 AC XY: 9701 AN XY: 74442

African (AFR) AF: 0.0618 AC: 2567 AN: 41558

American (AMR) AF: 0.0899 AC: 1375 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 914 AN: 3472

East Asian (EAS) AF: 0.308 AC: 1591 AN: 5164

South Asian (SAS) AF: 0.231 AC: 1116 AN: 4824

European-Finnish (FIN) AF: 0.142 AC: 1511 AN: 10612

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10259 AN: 68008

Other (OTH) AF: 0.122 AC: 257 AN: 2114

Alfa AF: 0.147 Hom.: 2902

Bravo AF: 0.125

Asia WGS AF: 0.242 AC: 843 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.152

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Quebec platelet disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.19
DANN	Benign	0.90
PhyloP100		-1.1
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: rs2227568; hg19: chr10-75673879; COSMIC: COSV65641301; COSMIC: COSV65641301;