11-73975507-G-C

Variant names:

• chr11-73975507-G-C
• rs748009040
• NM_003355.3:c.799C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003355.3(UCP2):​c.799C>G​(p.Arg267Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UCP2 NM_003355.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.251

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15618047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCP2	NM_003355.3	c.799C>G	p.Arg267Gly	missense_variant	Exon 7 of 8	ENST00000663595.2	NP_003346.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCP2	ENST00000663595.2	c.799C>G	p.Arg267Gly	missense_variant	Exon 7 of 8		NM_003355.3	ENSP00000499695.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250564 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458806 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725288

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.91	D;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.80	N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.28
Sift	Benign	0.38	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0	B;.
Vest4		0.49
MutPred		0.46		Loss of methylation at R267 (P = 0.0099);.;
MVP		0.83
MPC		0.070
ClinPred		0.12	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.67

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: rs748009040; hg19: chr11-73686552;