rs25683

Variant names:

• chr6-159775311-A-G
• rs25683
• NM_005891.3:c.632A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005891.3(ACAT2):​c.632A>G​(p.Lys211Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,613,274 control chromosomes in the GnomAD database, including 246,688 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (18101 hom., cov: 32)
  • Exomes 𝑓: 0.55 (228587 hom.)
• Consequence: ACAT2 NM_005891.3 missense, splice_region
• Scores: Splicing: ADA: 0.2030
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.65
• Publications: 50 publications found

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]

ACAT2 Gene-Disease associations (from GenCC):

• acetyl-CoA acetyltransferase-2 deficiency

  Inheritance: AR, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2847476E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAT2	NM_005891.3	c.632A>G	p.Lys211Arg	missense_variant, splice_region_variant	Exon 5 of 9	ENST00000367048.5	NP_005882.2
ACAT2	NM_001303253.1	c.719A>G	p.Lys240Arg	missense_variant, splice_region_variant	Exon 5 of 9		NP_001290182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAT2	ENST00000367048.5	c.632A>G	p.Lys211Arg	missense_variant, splice_region_variant	Exon 5 of 9	1	NM_005891.3	ENSP00000356015.4
ACAT2	ENST00000472052.1	n.26A>G		non_coding_transcript_exon_variant	Exon 1 of 4	2
ACAT2	ENST00000467951.1	n.*4A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69592 AN: 151968 Hom.: 18094 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.463

GnomAD2 exomes AF: 0.522 AC: 131212 AN: 251198 AF XY: 0.524

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.639

Gnomad ASJ exome AF: 0.557

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.552 AC: 806837 AN: 1461186 Hom.: 228587 Cov.: 42 AF XY: 0.550 AC XY: 399827 AN XY: 726912

African (AFR) AF: 0.212 AC: 7105 AN: 33470

American (AMR) AF: 0.632 AC: 28244 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14467 AN: 26130

East Asian (EAS) AF: 0.183 AC: 7254 AN: 39698

South Asian (SAS) AF: 0.502 AC: 43268 AN: 86218

European-Finnish (FIN) AF: 0.580 AC: 30967 AN: 53414

Middle Eastern (MID) AF: 0.484 AC: 2789 AN: 5768

European-Non Finnish (NFE) AF: 0.577 AC: 641558 AN: 1111390

Other (OTH) AF: 0.516 AC: 31185 AN: 60386

GnomAD4 genome AF: 0.458 AC: 69593 AN: 152088 Hom.: 18101 Cov.: 32 AF XY: 0.456 AC XY: 33915 AN XY: 74336

African (AFR) AF: 0.220 AC: 9128 AN: 41496

American (AMR) AF: 0.545 AC: 8322 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1953 AN: 3468

East Asian (EAS) AF: 0.183 AC: 950 AN: 5188

South Asian (SAS) AF: 0.496 AC: 2393 AN: 4822

European-Finnish (FIN) AF: 0.570 AC: 6018 AN: 10558

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.578 AC: 39264 AN: 67966

Other (OTH) AF: 0.458 AC: 968 AN: 2112

Alfa AF: 0.534 Hom.: 108906

Bravo AF: 0.445

TwinsUK AF: 0.566 AC: 2100

ALSPAC AF: 0.558 AC: 2150

ESP6500AA AF: 0.220 AC: 969

ESP6500EA AF: 0.574 AC: 4940

ExAC AF: 0.516 AC: 62606

Asia WGS AF: 0.352 AC: 1226 AN: 3478

EpiCase AF: 0.571

EpiControl AF: 0.572

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.00083	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.5	L
PhyloP100		8.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.58
Sift	Benign	0.043	D
Sift4G	Benign	0.14	T
Polyphen		0.92	P
Vest4		0.11
MPC		0.10
ClinPred		0.031	T
GERP RS		5.7
Varity_R		0.54
gMVP		0.67
Mutation Taster		=26/74	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.28
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: rs25683; hg19: chr6-160196343; COSMIC: COSV58460357; COSMIC: COSV58460357;