NM_005891.3:c.65A>G

Variant names:

• chr6-159762928-A-G
• rs199953042
• NM_005891.3:c.65A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005891.3(ACAT2):​c.65A>G​(p.Asn22Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,612,304 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. N22T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (1 hom.)
• Consequence: ACAT2 NM_005891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67
• Publications: 9 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09456614).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005891.3. 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
	ACAT2	NM_005891.3	MANE Select	c.65A>G	p.Asn22Ser	missense	Exon 2 of 9	NP_005882.2	Q9BWD1-1
	ACAT2	NM_001303253.1		c.152A>G	p.Asn51Ser	missense	Exon 2 of 9	NP_001290182.1	Q9BWD1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT2	ENST00000367048.5	TSL:1 MANE Select	c.65A>G	p.Asn22Ser	missense	Exon 2 of 9	ENSP00000356015.4	Q9BWD1-1
	ACAT2	ENST00000869581.1		c.65A>G	p.Asn22Ser	missense	Exon 2 of 9	ENSP00000539640.1
	ACAT2	ENST00000869587.1		c.65A>G	p.Asn22Ser	missense	Exon 2 of 9	ENSP00000539646.1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000132 AC: 33 AN: 249328 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000498

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000822 AC: 120 AN: 1460046 Hom.: 1 Cov.: 32 AF XY: 0.0000909 AC XY: 66 AN XY: 726392

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.000406 AC: 18 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86112

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111196

Other (OTH) AF: 0.000133 AC: 8 AN: 60270

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74454

African (AFR) AF: 0.0000481 AC: 2 AN: 41540

American (AMR) AF: 0.00242 AC: 37 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000859 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.083
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.16
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.023	B
Vest4		0.35
MVP		0.40
MPC		0.10
ClinPred		0.074	T
GERP RS		1.3
PromoterAI		0.0043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.67
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199953042; hg19: chr6-160183960; COSMIC: COSV65455168; COSMIC: COSV65455168;