11-73980729-T-C

Variant names:

• chr11-73980729-T-C
• rs17132534
• NM_003355.3:c.-100+747A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003355.3(UCP2):​c.-100+747A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 152,302 control chromosomes in the GnomAD database, including 851 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.085 (851 hom., cov: 32)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: UCP2 NM_003355.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.665
• Publications: 22 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCP2	NM_003355.3	MANE Select	c.-100+747A>G		intron	N/A	NP_003346.2
	UCP2	NM_001381943.1		c.-157A>G		5_prime_UTR	Exon 3 of 9	NP_001368872.1
	UCP2	NM_001381944.1		c.-100+747A>G		intron	N/A	NP_001368873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCP2	ENST00000663595.2	MANE Select	c.-100+747A>G		intron	N/A	ENSP00000499695.1
	UCP2	ENST00000310473.10	TSL:1	c.-137-677A>G		intron	N/A	ENSP00000312029.3
	UCP2	ENST00000539764.1	TSL:3	c.-157A>G		5_prime_UTR	Exon 1 of 2	ENSP00000438230.1

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12838 AN: 152148 Hom.: 847 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0661

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0440

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0928

GnomAD4 exome AF: 0.0556 AC: 2 AN: 36 Hom.: 0 Cov.: 0 AF XY: 0.0714 AC XY: 2 AN XY: 28

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0357 AC: 1 AN: 28

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0845 AC: 12869 AN: 152266 Hom.: 851 Cov.: 32 AF XY: 0.0822 AC XY: 6118 AN XY: 74464

African (AFR) AF: 0.180 AC: 7489 AN: 41540

American (AMR) AF: 0.0660 AC: 1009 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0438 AC: 211 AN: 4814

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10622

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0478 AC: 3248 AN: 68018

Other (OTH) AF: 0.0914 AC: 193 AN: 2112

Alfa AF: 0.0619 Hom.: 772

Bravo AF: 0.0931

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.7
DANN	Benign	0.68
PhyloP100		-0.67
PromoterAI		0.0064	Neutral
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: rs17132534; hg19: chr11-73691774;