chr1-39769869-C-G

Variant names:

• chr1-39769869-C-G
• rs544321343
• NM_022120.2:c.1387G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022120.2(OXCT2):​c.1387G>C​(p.Val463Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 150,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OXCT2 NM_022120.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022120.2. 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
	OXCT2	NM_022120.2	MANE Select	c.1387G>C	p.Val463Leu	missense	Exon 1 of 1	NP_071403.1	Q9BYC2
	BMP8B	NM_001720.5	MANE Select	c.673+4439G>C		intron	N/A	NP_001711.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OXCT2	ENST00000327582.5	TSL:6 MANE Select	c.1387G>C	p.Val463Leu	missense	Exon 1 of 1	ENSP00000361914.1	Q9BYC2
	BMP8B	ENST00000372827.8	TSL:1 MANE Select	c.673+4439G>C		intron	N/A	ENSP00000361915.3	P34820-1

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150314 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000985

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

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249672 AF XY: 0.00000740

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000411 AC: 6 AN: 1460670 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726648

African (AFR) AF: 0.0000599 AC: 2 AN: 33396

American (AMR) AF: 0.0000448 AC: 2 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111494

Other (OTH) AF: 0.0000166 AC: 1 AN: 60326

GnomAD4 genome AF: 0.0000266 AC: 4 AN: 150432 Hom.: 0 Cov.: 21 AF XY: 0.0000408 AC XY: 3 AN XY: 73452

African (AFR) AF: 0.0000982 AC: 4 AN: 40748

American (AMR) AF: 0.00 AC: 0 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 4954

South Asian (SAS) AF: 0.00 AC: 0 AN: 4664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10484

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67682

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.0
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.63		Gain of catalytic residue at V463 (P = 0.0013)
MVP		0.93
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.45
gMVP		0.76
Mutation Taster		=93/7	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: rs544321343; hg19: chr1-40235541;