12-109237224-T-C

Variant names:

• chr12-109237224-T-C
• rs2241220
• NM_001093.4:c.4506T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001093.4(ACACB):​c.4506T>C​(p.Leu1502Leu) 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
• Publications: 39 publications found

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]

ACACB Gene-Disease associations (from GenCC):

• isolated cleft palate

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001093.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	NM_001093.4	MANE Select	c.4506T>C	p.Leu1502Leu	synonymous	Exon 34 of 53	NP_001084.3
	ACACB	NM_001412734.1		c.4506T>C	p.Leu1502Leu	synonymous	Exon 35 of 54	NP_001399663.1
	ACACB	NM_001412735.1		c.4506T>C	p.Leu1502Leu	synonymous	Exon 34 of 53	NP_001399664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	ENST00000338432.12	TSL:1 MANE Select	c.4506T>C	p.Leu1502Leu	synonymous	Exon 34 of 53	ENSP00000341044.7
	ACACB	ENST00000377848.7	TSL:1	c.4506T>C	p.Leu1502Leu	synonymous	Exon 33 of 52	ENSP00000367079.3
	ACACB	ENST00000377854.9	TSL:5	c.504T>C	p.Leu168Leu	synonymous	Exon 33 of 47	ENSP00000367085.6

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

GnomAD2 exomes AF: 0.829 AC: 208512 AN: 251480 AF XY: 0.827

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 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

African (AFR) AF: 0.731 AC: 24481 AN: 33478

American (AMR) AF: 0.902 AC: 40360 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.867 AC: 22666 AN: 26136

East Asian (EAS) AF: 0.711 AC: 28231 AN: 39700

South Asian (SAS) AF: 0.782 AC: 67445 AN: 86258

European-Finnish (FIN) AF: 0.836 AC: 44677 AN: 53418

Middle Eastern (MID) AF: 0.823 AC: 4745 AN: 5768

European-Non Finnish (NFE) AF: 0.840 AC: 933827 AN: 1112008

Other (OTH) AF: 0.825 AC: 49816 AN: 60396

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

African (AFR) AF: 0.734 AC: 30403 AN: 41434

American (AMR) AF: 0.874 AC: 13341 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 2978 AN: 3470

East Asian (EAS) AF: 0.730 AC: 3779 AN: 5178

South Asian (SAS) AF: 0.778 AC: 3747 AN: 4816

European-Finnish (FIN) AF: 0.838 AC: 8855 AN: 10570

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.842 AC: 57225 AN: 67992

Other (OTH) AF: 0.820 AC: 1733 AN: 2114

Alfa AF: 0.832 Hom.: 241419

Bravo AF: 0.807

Asia WGS AF: 0.749 AC: 2605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.9
DANN	Benign	0.66
PhyloP100		1.1
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2241220; hg19: chr12-109675029; COSMIC: COSV58134294; COSMIC: COSV58134294;