rs45526034

Variant names:

• chr11-73975556-G-A
• rs45526034
• NM_003355.3:c.750C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003355.3(UCP2):​c.750C>T​(p.Tyr250Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,614,124 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (56 hom.)
• Consequence: UCP2 NM_003355.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.53
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 11-73975556-G-A is Benign according to our data. Variant chr11-73975556-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1896/152312) while in subpopulation AFR AF = 0.0436 (1812/41556). AF 95% confidence interval is 0.0419. There are 38 homozygotes in GnomAd4. There are 888 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1896 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCP2	NM_003355.3	MANE Select	c.750C>T	p.Tyr250Tyr	synonymous	Exon 7 of 8	NP_003346.2
	UCP2	NM_001381943.1		c.750C>T	p.Tyr250Tyr	synonymous	Exon 8 of 9	NP_001368872.1	P55851
	UCP2	NM_001381944.1		c.750C>T	p.Tyr250Tyr	synonymous	Exon 7 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.750C>T	p.Tyr250Tyr	synonymous	Exon 7 of 8	ENSP00000499695.1	P55851
	UCP2	ENST00000310473.11	TSL:1	c.750C>T	p.Tyr250Tyr	synonymous	Exon 8 of 9	ENSP00000312029.3
	UCP2	ENST00000880151.1		c.783C>T	p.Tyr261Tyr	synonymous	Exon 7 of 8	ENSP00000550210.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1889 AN: 152194 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00298 AC: 748 AN: 251416 AF XY: 0.00236

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00133 AC: 1943 AN: 1461812 Hom.: 56 Cov.: 32 AF XY: 0.00115 AC XY: 838 AN XY: 727192

African (AFR) AF: 0.0489 AC: 1637 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00245 AC: 14 AN: 5714

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1112006

Other (OTH) AF: 0.00288 AC: 174 AN: 60384

GnomAD4 genome AF: 0.0124 AC: 1896 AN: 152312 Hom.: 38 Cov.: 32 AF XY: 0.0119 AC XY: 888 AN XY: 74476

African (AFR) AF: 0.0436 AC: 1812 AN: 41556

American (AMR) AF: 0.00386 AC: 59 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00653 Hom.: 14

Bravo AF: 0.0143

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.2
DANN	Benign	0.49
PhyloP100		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs45526034; hg19: chr11-73686601;