12-109237224-T-C

Position:

• chr12-109237224-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001093.4(ACACB):​c.4506T>C​(p.Leu1502=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 1,613,930 control chromosomes in the GnomAD database, including 556,875 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (50050 hom., cov: 31)
  • Exomes 𝑓: 0.83 (506825 hom.)
• Consequence: ACACB NM_001093.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10

Genes affected

ACACB (HGNC:85): (acetyl-CoA carboxylase beta) Acetyl-CoA carboxylase (ACC) is a complex multifunctional enzyme system. ACC is a biotin-containing enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ACC-beta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA transferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. [provided by RefSeq, Oct 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACACB	NM_001093.4	c.4506T>C	p.Leu1502=	synonymous_variant	34/53	ENST00000338432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACACB	ENST00000338432.12	c.4506T>C	p.Leu1502=	synonymous_variant	34/53	1	NM_001093.4	P1
ACACB	ENST00000377848.7	c.4506T>C	p.Leu1502=	synonymous_variant	33/52	1		P1
ACACB	ENST00000377854.9	c.504T>C	p.Leu168=	synonymous_variant	33/47	5
ACACB	ENST00000538526.5	c.507T>C	p.Leu169=	synonymous_variant, NMD_transcript_variant	6/26	5

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122908 AN: 151924 Hom.: 50010 Cov.: 31

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.874

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.838

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.822

GnomAD3 exomes AF: 0.829 AC: 208512 AN: 251480 Hom.: 86858 AF XY: 0.827 AC XY: 112425 AN XY: 135914

Gnomad AFR exome AF: 0.726

Gnomad AMR exome AF: 0.907

Gnomad ASJ exome AF: 0.869

Gnomad EAS exome AF: 0.743

Gnomad SAS exome AF: 0.781

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.842

GnomAD4 exome AF: 0.832 AC: 1216248 AN: 1461886 Hom.: 506825 Cov.: 73 AF XY: 0.831 AC XY: 604468 AN XY: 727246

Gnomad4 AFR exome AF: 0.731

Gnomad4 AMR exome AF: 0.902

Gnomad4 ASJ exome AF: 0.867

Gnomad4 EAS exome AF: 0.711

Gnomad4 SAS exome AF: 0.782

Gnomad4 FIN exome AF: 0.836

Gnomad4 NFE exome AF: 0.840

Gnomad4 OTH exome AF: 0.825

GnomAD4 genome AF: 0.809 AC: 123004 AN: 152044 Hom.: 50050 Cov.: 31 AF XY: 0.810 AC XY: 60194 AN XY: 74316

Gnomad4 AFR AF: 0.734

Gnomad4 AMR AF: 0.874

Gnomad4 ASJ AF: 0.858

Gnomad4 EAS AF: 0.730

Gnomad4 SAS AF: 0.778

Gnomad4 FIN AF: 0.838

Gnomad4 NFE AF: 0.842

Gnomad4 OTH AF: 0.820

Alfa AF: 0.836 Hom.: 127105

Bravo AF: 0.807

Asia WGS AF: 0.749 AC: 2605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.9
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2241220; hg19: chr12-109675029; COSMIC: COSV58134294; COSMIC: COSV58134294;