chr14-73569794-C-G

Variant names:

• chr14-73569794-C-G
• rs774582968
• NM_006821.6:c.554C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T185A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ACOT2 NM_006821.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.260
• Publications: 3 publications found

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]

ENSG00000258603 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006821.6. 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
	ACOT2	NM_006821.6	MANE Select	c.554C>G	p.Thr185Arg	missense	Exon 1 of 3	NP_006812.3
	ACOT2	NM_001364178.1		c.554C>G	p.Thr185Arg	missense	Exon 1 of 3	NP_001351107.1
	ACOT2	NM_001364177.1		c.52+398C>G		intron	N/A	NP_001351106.1	B3KSA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACOT2	ENST00000238651.10	TSL:1 MANE Select	c.554C>G	p.Thr185Arg	missense	Exon 1 of 3	ENSP00000238651.5	P49753-1
	ACOT2	ENST00000613168.1	TSL:1	c.494C>G	p.Thr165Arg	missense	Exon 1 of 3	ENSP00000477685.1	A0A087WT95
	ACOT2	ENST00000864002.1		c.554C>G	p.Thr185Arg	missense	Exon 1 of 3	ENSP00000534061.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152052 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.0000402 AC: 9 AN: 223802 AF XY: 0.0000486

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.0000227 AC: 1 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 85174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4964

European-Non Finnish (NFE) AF: 0.0000324 AC: 35 AN: 1080058

Other (OTH) AF: 0.00 AC: 0 AN: 59016

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152052 Hom.: 1 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000435 Hom.: 2

ExAC AF: 0.0000512 AC: 6

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	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
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.26
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.046	D
Sift4G	Uncertain	0.021	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
Mutation Taster		=99/1	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: rs774582968; hg19: chr14-74036498;