rs25683

Positions:

• chr6-159775311-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2847476E-4).
• BP6: Variant 6-159775311-A-G is Benign according to our data. Variant chr6-159775311-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ACAT2	NM_005891.3	c.632A>G	p.Lys211Arg	missense_variant, splice_region_variant	5/9	ENST00000367048.5	NP_005882.2
ACAT2	NM_001303253.1	c.719A>G	p.Lys240Arg	missense_variant, splice_region_variant	5/9		NP_001290182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAT2	ENST00000367048.5	c.632A>G	p.Lys211Arg	missense_variant, splice_region_variant	5/9	1	NM_005891.3	ENSP00000356015	P1
ACAT2	ENST00000472052.1	n.26A>G		non_coding_transcript_exon_variant	1/4	2
ACAT2	ENST00000467951.1			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

GnomAD3 exomes AF: 0.522 AC: 131212 AN: 251198 Hom.: 36777 AF XY: 0.524 AC XY: 71213 AN XY: 135776

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 SAS exome AF: 0.501

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

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.632

Gnomad4 ASJ exome AF: 0.554

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.502

Gnomad4 FIN exome AF: 0.580

Gnomad4 NFE exome AF: 0.577

Gnomad4 OTH exome AF: 0.516

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

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.545

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.496

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.578

Gnomad4 OTH AF: 0.458

Alfa AF: 0.546 Hom.: 57471

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
MutationTaster	Benign	2.5e-8	P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs25683; hg19: chr6-160196343; COSMIC: COSV58460357; COSMIC: COSV58460357;