1-39770423-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022120.2(OXCT2):​c.833G>T​(p.Arg278Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,608,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 22)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

OXCT2
NM_022120.2 missense

Scores

3
5
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.849
Variant links:
Genes affected
OXCT2 (HGNC:18606): (3-oxoacid CoA-transferase 2) The protein encoded by this gene catalyzes the transfer of a CoA group from succinate to acetoacetate and is an important enzyme in ketone body catabolism. The encoded protein localizes to the mitochondrion. This gene is intronless, and a pseudogene of this gene is located elsewhere on chromosome 1. [provided by RefSeq, Aug 2016]
BMP8B (HGNC:1075): (bone morphogenetic protein 8b) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The encoded protein stimulates thermogenesis in brown adipose tissue. Expression of this gene may be downregulated in pancreatic cancer. This gene may have arose from a gene duplication event and its gene duplicate is also present on chromosome 1. [provided by RefSeq, Jul 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29833114).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OXCT2NM_022120.2 linkuse as main transcriptc.833G>T p.Arg278Leu missense_variant 1/1 ENST00000327582.5 NP_071403.1 Q9BYC2
BMP8BNM_001720.5 linkuse as main transcriptc.673+3885G>T intron_variant ENST00000372827.8 NP_001711.2 P34820-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OXCT2ENST00000327582.5 linkuse as main transcriptc.833G>T p.Arg278Leu missense_variant 1/16 NM_022120.2 ENSP00000361914.1 Q9BYC2
BMP8BENST00000372827.8 linkuse as main transcriptc.673+3885G>T intron_variant 1 NM_001720.5 ENSP00000361915.3 P34820-1

Frequencies

GnomAD3 genomes
AF:
0.00000673
AC:
1
AN:
148694
Hom.:
0
Cov.:
22
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000213
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1459828
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000254
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000672
AC:
1
AN:
148810
Hom.:
0
Cov.:
22
AF XY:
0.0000137
AC XY:
1
AN XY:
72770
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000213
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 10, 2023The c.833G>T (p.R278L) alteration is located in exon 1 (coding exon 1) of the OXCT2 gene. This alteration results from a G to T substitution at nucleotide position 833, causing the arginine (R) at amino acid position 278 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Uncertain
0.046
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.072
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.59
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.30
T
MetaSVM
Uncertain
-0.062
T
MutationAssessor
Pathogenic
3.0
M
PrimateAI
Benign
0.32
T
PROVEAN
Pathogenic
-6.0
D
REVEL
Uncertain
0.42
Sift
Benign
0.060
T
Sift4G
Uncertain
0.037
D
Polyphen
0.99
D
Vest4
0.26
MutPred
0.44
Loss of MoRF binding (P = 0.0094);
MVP
0.94
ClinPred
0.99
D
GERP RS
1.7
Varity_R
0.17
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1262186887; hg19: chr1-40236095; COSMIC: COSV59594750; API