chr11-73975084-C-G

Variant names:

• chr11-73975084-C-G
• rs546507804
• NM_003355.3:c.853G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003355.3(UCP2):​c.853G>C​(p.Val285Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UCP2 NM_003355.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCP2	NM_003355.3	c.853G>C	p.Val285Leu	missense_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.853G>C	p.Val285Leu	missense_variant	Exon 8 of 8		NM_003355.3	ENSP00000499695.1
UCP2	ENST00000310473.9	c.853G>C	p.Val285Leu	missense_variant	Exon 9 of 9	1		ENSP00000312029.3
UCP2	ENST00000536983.5	c.672G>C	p.Thr224Thr	synonymous_variant	Exon 7 of 7	5		ENSP00000441147.1
UCP2	ENST00000544615.5	n.772G>C		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461578 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74240

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.26	T;T
Polyphen		0.018	B;.
Vest4		0.65
MutPred		0.72		Loss of MoRF binding (P = 0.1002);.;
MVP		0.72
MPC		0.064
ClinPred		0.81	D
GERP RS		6.0
Varity_R		0.44
gMVP		0.92

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: rs546507804; hg19: chr11-73686129;