chr6-159767007-T-G

Position:

• chr6-159767007-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005891.3(ACAT2):​c.193T>G​(p.Cys65Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACAT2 NM_005891.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

Genes affected

ACAT2 (HGNC:94): (acetyl-CoA acetyltransferase 2) The product of this gene is an enzyme involved in lipid metabolism, and it encodes cytosolic acetoacetyl-CoA thiolase. This gene shows complementary overlapping with the 3-prime region of the TCP1 gene in both mouse and human. These genes are encoded on opposite strands of DNA, as well as in opposite transcriptional orientation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

ACMG classification

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=0.34393263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAT2	NM_005891.3	c.193T>G	p.Cys65Gly	missense_variant, splice_region_variant	3/9	ENST00000367048.5
ACAT2	NM_001303253.1	c.280T>G	p.Cys94Gly	missense_variant, splice_region_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAT2	ENST00000367048.5	c.193T>G	p.Cys65Gly	missense_variant, splice_region_variant	3/9	1	NM_005891.3	P1
ACAT2	ENST00000467951.1	n.421T>G		splice_region_variant, non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The c.193T>G (p.C65G) alteration is located in exon 3 (coding exon 3) of the ACAT2 gene. This alteration results from a T to G substitution at nucleotide position 193, causing the cysteine (C) at amino acid position 65 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0081
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.095	N
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.13	N
REVEL	Uncertain	0.37
Sift	Benign	0.27	T
Sift4G	Benign	0.38	T
Polyphen		0.070	B
Vest4		0.44
MVP		0.94
MPC		0.24
ClinPred		0.30	T
GERP RS		5.7
Varity_R		0.34
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-160188039;