NM_006821.6:c.554C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006821.6(ACOT2):​c.554C>G​(p.Thr185Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000432 in 1,574,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ACOT2
NM_006821.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.260
Variant links:
Genes affected
ACOT2 (HGNC:18431): (acyl-CoA thioesterase 2) This gene encodes a member of the acyl-CoA thioesterase protein family, and is one of four acyl-CoA hydrolase genes located in a cluster on chromosome 14. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]
HEATR4 (HGNC:16761): (HEAT repeat containing 4) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0051775575).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACOT2NM_006821.6 linkc.554C>G p.Thr185Arg missense_variant Exon 1 of 3 ENST00000238651.10 NP_006812.3 P49753-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACOT2ENST00000238651.10 linkc.554C>G p.Thr185Arg missense_variant Exon 1 of 3 1 NM_006821.6 ENSP00000238651.5 P49753-1
ACOT2ENST00000613168.1 linkc.494C>G p.Thr165Arg missense_variant Exon 1 of 3 1 ENSP00000477685.1 A0A087WT95
ACOT2ENST00000538782.2 linkn.96+398C>G intron_variant Intron 2 of 3 2 ENSP00000440961.2 F6VI00
ENSG00000258603ENST00000664243.1 linkn.63-11822G>C intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
AF:
0.000210
AC:
32
AN:
152052
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.0231
Gnomad AMR
AF:
0.0000655
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000402
AC:
9
AN:
223802
Hom.:
0
AF XY:
0.0000486
AC XY:
6
AN XY:
123574
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000302
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000818
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
36
AN:
1422068
Hom.:
0
Cov.:
30
AF XY:
0.0000297
AC XY:
21
AN XY:
707842
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000227
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:
0.0000324
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000210
AC:
32
AN:
152052
Hom.:
1
Cov.:
33
AF XY:
0.000188
AC XY:
14
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000435
Hom.:
2
ExAC
AF:
0.0000512
AC:
6

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.554C>G (p.T185R) alteration is located in exon 1 (coding exon 1) of the ACOT2 gene. This alteration results from a C to G substitution at nucleotide position 554, causing the threonine (T) at amino acid position 185 to be replaced by an arginine (R). 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
Benign
0.11
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
15
DANN
Benign
0.89
DEOGEN2
Benign
0.015
T;T;.
Eigen
Benign
-0.98
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.046
N
LIST_S2
Benign
0.15
T;T;T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.0052
T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.1
M;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.3
N;.;.
REVEL
Benign
0.12
Sift
Benign
0.046
D;.;.
Sift4G
Uncertain
0.021
D;D;D
Polyphen
0.31
B;.;.
Vest4
0.20
MVP
0.75
ClinPred
0.14
T
GERP RS
1.4
Varity_R
0.16
gMVP
0.74

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

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

Other links and lift over

dbSNP: rs774582968; hg19: chr14-74036498; API