NM_003355.3:c.164C>T

Variant names:

• chr11-73978059-G-A
• rs660339
• NM_003355.3:c.164C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:5
• Conservation: PhyloP100: 1.01
• Publications: 241 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCP2	NM_003355.3	MANE Select	c.164C>T	p.Ala55Val	missense	Exon 4 of 8	NP_003346.2
	UCP2	NM_001381943.1		c.164C>T	p.Ala55Val	missense	Exon 5 of 9	NP_001368872.1	P55851
	UCP2	NM_001381944.1		c.164C>T	p.Ala55Val	missense	Exon 4 of 8	NP_001368873.1	P55851

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCP2	ENST00000663595.2	MANE Select	c.164C>T	p.Ala55Val	missense	Exon 4 of 8	ENSP00000499695.1	P55851
	UCP2	ENST00000310473.11	TSL:1	c.164C>T	p.Ala55Val	missense	Exon 5 of 9	ENSP00000312029.3
	UCP2	ENST00000880151.1		c.164C>T	p.Ala55Val	missense	Exon 4 of 8	ENSP00000550210.1

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

GnomAD2 exomes AF: 0.412 AC: 103341 AN: 250864 AF XY: 0.404

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 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

African (AFR) AF: 0.453 AC: 15148 AN: 33476

American (AMR) AF: 0.464 AC: 20724 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 8794 AN: 26136

East Asian (EAS) AF: 0.446 AC: 17721 AN: 39696

South Asian (SAS) AF: 0.340 AC: 29365 AN: 86250

European-Finnish (FIN) AF: 0.460 AC: 24584 AN: 53390

Middle Eastern (MID) AF: 0.324 AC: 1867 AN: 5766

European-Non Finnish (NFE) AF: 0.409 AC: 455075 AN: 1111950

Other (OTH) AF: 0.403 AC: 24312 AN: 60390

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

African (AFR) AF: 0.454 AC: 18812 AN: 41444

American (AMR) AF: 0.450 AC: 6877 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1128 AN: 3468

East Asian (EAS) AF: 0.426 AC: 2202 AN: 5168

South Asian (SAS) AF: 0.339 AC: 1634 AN: 4818

European-Finnish (FIN) AF: 0.467 AC: 4941 AN: 10590

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.412 AC: 28022 AN: 67936

Other (OTH) AF: 0.402 AC: 847 AN: 2106

Alfa AF: 0.410 Hom.: 43227

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Benign	0.17	T
Polyphen		0.0	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
Mutation Taster		=92/8	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: rs660339; hg19: chr11-73689104; COSMIC: COSV60104349; COSMIC: COSV60104349;