rs371789455

Variant names:

• chr11-73976909-C-G
• rs371789455
• NM_003355.3:c.446G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-73976909-C-G
• chr11-73976909-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003355.3(UCP2):​c.446G>C​(p.Arg149Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UCP2 NM_003355.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.363165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCP2	NM_003355.3	c.446G>C	p.Arg149Pro	missense_variant	Exon 5 of 8	ENST00000663595.2	NP_003346.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCP2	ENST00000663595.2	c.446G>C	p.Arg149Pro	missense_variant	Exon 5 of 8		NM_003355.3	ENSP00000499695.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727106

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111848

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;T;.;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.85	L;.;.;.
PhyloP100		1.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.028	D;T;D;D
Sift4G	Uncertain	0.025	D;T;D;.
Polyphen		0.83	P;D;.;.
Vest4		0.51
MutPred		0.43		Loss of MoRF binding (P = 0.0101);Loss of MoRF binding (P = 0.0101);.;.;
MVP		0.87
MPC		0.22
ClinPred		0.90	D
GERP RS		5.0
PromoterAI		0.020	Neutral
Varity_R		0.45
gMVP		0.86
Mutation Taster		=66/34	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: rs371789455; hg19: chr11-73687954;