11-73975005-G-C

Variant names:

• chr11-73975005-G-C
• rs114649509
• NM_003355.3:c.*2C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003355.3(UCP2):​c.*2C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,578,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: UCP2 NM_003355.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71
• Publications: 2 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BS2: High AC in GnomAd4 at 170 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCP2	NM_003355.3	c.*2C>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000663595.2	NP_003346.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCP2	ENST00000663595.2	c.*2C>G		3_prime_UTR_variant	Exon 8 of 8		NM_003355.3	ENSP00000499695.1
UCP2	ENST00000310473.10	c.*2C>G		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000312029.3
UCP2	ENST00000544615.5	n.851C>G		non_coding_transcript_exon_variant	Exon 5 of 5	2
UCP2	ENST00000536983.5	c.*73C>G		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000441147.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 169 AN: 136008 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000548

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000218 AC: 53 AN: 243456 AF XY: 0.000212

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 155 AN: 1442314 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 79 AN XY: 717264

African (AFR) AF: 0.00406 AC: 134 AN: 33030

American (AMR) AF: 0.000206 AC: 9 AN: 43688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 38624

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099450

Other (OTH) AF: 0.000169 AC: 10 AN: 59086

GnomAD4 genome AF: 0.00125 AC: 170 AN: 136130 Hom.: 1 Cov.: 31 AF XY: 0.00116 AC XY: 77 AN XY: 66492

African (AFR) AF: 0.00429 AC: 163 AN: 38018

American (AMR) AF: 0.000548 AC: 7 AN: 12780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3204

East Asian (EAS) AF: 0.00 AC: 0 AN: 4802

South Asian (SAS) AF: 0.00 AC: 0 AN: 4434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60958

Other (OTH) AF: 0.00 AC: 0 AN: 1838

Alfa AF: 0.0000559 Hom.: 0

Bravo AF: 0.00133

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 01, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.3
DANN	Benign	0.71
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

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: rs114649509; hg19: chr11-73686050;