rs45541732

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003355.3(UCP2):c.227G>A(p.Arg76Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,614,214 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 3 hom. )

Consequence

UCP2
NM_003355.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.05

Publications

6 publications found

Variant links:

Genes affected

UCP2 (HGNC:12518): (uncoupling protein 2) Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Tissue specificity occurs for the different UCPs and the exact methods of how UCPs transfer H+/OH- are not known. UCPs contain the three homologous protein domains of MACPs. This gene is expressed in many tissues, with the greatest expression in skeletal muscle. It is thought to play a role in nonshivering thermogenesis, obesity and diabetes. Chromosomal order is 5'-UCP3-UCP2-3'. [provided by RefSeq, Jul 2008]

UCP2 Gene-Disease associations (from GenCC):

hyperinsulinism due to UCP2 deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

UCP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011333287).

BP6

Variant 11-73977996-C-T is Benign according to our data. Variant chr11-73977996-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 437199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 359 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003355.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UCP2	NM_003355.3	MANE Select	c.227G>A	p.Arg76Gln	missense	Exon 4 of 8	NP_003346.2
UCP2	NM_001381943.1		c.227G>A	p.Arg76Gln	missense	Exon 5 of 9	NP_001368872.1	P55851
UCP2	NM_001381944.1		c.227G>A	p.Arg76Gln	missense	Exon 4 of 8	NP_001368873.1	P55851

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UCP2	ENST00000663595.2	MANE Select	c.227G>A	p.Arg76Gln	missense	Exon 4 of 8	ENSP00000499695.1	P55851
UCP2	ENST00000310473.11	TSL:1	c.227G>A	p.Arg76Gln	missense	Exon 5 of 9	ENSP00000312029.3
UCP2	ENST00000880151.1		c.227G>A	p.Arg76Gln	missense	Exon 4 of 8	ENSP00000550210.1

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

357

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00811

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000704

AC:

177

AN:

251338

AF XY:

0.000611

show subpopulations

Gnomad AFR exome

AF:

0.00874

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000404

AC:

591

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000384

AC XY:

279

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00980

AC:

328

AN:

33480

American (AMR)

AF:

0.000425

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000162

AC:

180

AN:

1112010

Other (OTH)

AF:

0.000745

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152336

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00813

AC:

338

AN:

41570

American (AMR)

AF:

0.000588

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.00296

ESP6500AA

AF:

0.0105

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000848

AC:

103

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 4 (1)

UCP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.026

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.2

PhyloP100

2.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.32

Sift

Benign

0.30

Sift4G

Benign

0.52

Polyphen

0.10

Vest4

0.45

MVP

0.84

MPC

0.077

ClinPred

0.016

GERP RS

6.1

Varity_R

0.21

gMVP

0.71

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over