Genetic Variant UPK2:p.Gly93Asp (chr11-118957277-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006760.4(UPK2):c.278G>A(p.Gly93Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,614,160 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 28 hom. )

Consequence

UPK2
NM_006760.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.33

Variant links:

Genes affected

UPK2 (HGNC:12579): (uroplakin 2) This gene encodes one of the proteins of the highly conserved urothelium-specific integral membrane proteins of the asymmetric unit membrane which forms urothelium apical plaques in mammals. The asymmetric unit membrane is believed to strengthen the urothelium by preventing cell rupture during bladder distention. The encoded protein is expressed in the peripheral blood of bladder cancer patients with transitional cell carcinomas.[provided by RefSeq, Sep 2009]

UPK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069190264).

BP6

Variant 11-118957277-G-A is Benign according to our data. Variant chr11-118957277-G-A is described in ClinVar as [Benign]. Clinvar id is 784218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00186 (2713/1461880) while in subpopulation AMR AF= 0.0309 (1380/44724). AF 95% confidence interval is 0.0295. There are 28 homozygotes in gnomad4_exome. There are 1240 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK2	NM_006760.4 link	c.278G>A	p.Gly93Asp	missense_variant	Exon 3 of 5	ENST00000264031.3	NP_006751.1	O00526

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK2	ENST00000264031.3 link	c.278G>A	p.Gly93Asp	missense_variant	Exon 3 of 5	1	NM_006760.4	ENSP00000264031.2		O00526
UPK2	ENST00000534788.1 link	n.392G>A		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

474

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00847

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00652

AC:

1640

AN:

251428

Hom.:

AF XY:

0.00536

AC XY:

728

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.0337

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00794

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00947

Gnomad NFE exome

AF:

0.000651

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00186

AC:

2713

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1240

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00889

Gnomad4 SAS exome

AF:

0.000684

Gnomad4 FIN exome

AF:

0.00833

Gnomad4 NFE exome

AF:

0.000298

Gnomad4 OTH exome

AF:

0.00215

GnomAD4 genome

AF:

0.00311

AC:

474

AN:

152280

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

275

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.0145

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00849

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0103

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.00383

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.00530

AC:

643

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.90

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.32

Sift

Benign

0.26

Sift4G

Benign

0.36

Polyphen

0.98

Vest4

0.54

MVP

0.51

MPC

0.61

ClinPred

0.028

GERP RS

6.0

Varity_R

0.39

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over