rs660339

chr11-73978059-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003355.3(UCP2):c.164C>T(p.Ala55Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,613,752 control chromosomes in the GnomAD database, including 137,095 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (13830 hom., cov: 32)
  • Exomes 𝑓: 0.41 (123265 hom.)
• Consequence: UCP2 NM_003355.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.01

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013258755).
• BP6: Variant 11-73978059-G-A is Benign according to our data. Variant chr11-73978059-G-A is described in ClinVar as [Benign]. Clinvar id is 130697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCP2	NM_003355.3	c.164C>T	p.Ala55Val	missense_variant	4/8	ENST00000663595.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCP2	ENST00000663595.2	c.164C>T	p.Ala55Val	missense_variant	4/8		NM_003355.3	P1
UCP2	ENST00000310473.9	c.164C>T	p.Ala55Val	missense_variant	5/9	1		P1
UCP2	ENST00000536983.5	c.164C>T	p.Ala55Val	missense_variant	4/7	5
UCP2	ENST00000544615.5	n.83C>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64775 AN: 151882 Hom.: 13832 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.406

GnomAD3 exomes AF: 0.412 AC: 103341 AN: 250864 Hom.: 21712 AF XY: 0.404 AC XY: 54795 AN XY: 135646

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.464

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.398

Gnomad SAS exome AF: 0.343

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.409 AC: 597590 AN: 1461752 Hom.: 123265 Cov.: 73 AF XY: 0.406 AC XY: 295093 AN XY: 727178

Gnomad4 AFR exome AF: 0.453

Gnomad4 AMR exome AF: 0.464

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.446

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.460

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.403

GnomAD4 genome AF: 0.426 AC: 64790 AN: 152000 Hom.: 13830 Cov.: 32 AF XY: 0.427 AC XY: 31714 AN XY: 74308

Gnomad4 AFR AF: 0.454

Gnomad4 AMR AF: 0.450

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.402

Alfa AF: 0.405 Hom.: 28778

Bravo AF: 0.428

TwinsUK AF: 0.420 AC: 1558

ALSPAC AF: 0.424 AC: 1633

ESP6500AA AF: 0.437 AC: 1923

ESP6500EA AF: 0.408 AC: 3503

ExAC AF: 0.411 AC: 49899

Asia WGS AF: 0.386 AC: 1342 AN: 3478

EpiCase AF: 0.397

EpiControl AF: 0.389

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 23132673, 10557023, 19950601, 19368944, 10071761, 19653005, 25158045, 18956255, 21751002, 23537071, 19895332) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.87	D;D;.
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	0.99	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.91	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.12
MPC		0.057
ClinPred		0.011	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs660339; hg19: chr11-73689104; COSMIC: COSV60104349; COSMIC: COSV60104349;