rs2075259

Variant names:

• chr12-109254186-A-G
• rs2075259
• NM_001093.4:c.6046-28A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-109254186-A-G
• chr12-109254186-A-T

Variant summary

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

The NM_001093.4(ACACB):​c.6046-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 1,611,184 control chromosomes in the GnomAD database, including 517,634 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.77 (45756 hom., cov: 30)
  • Exomes 𝑓: 0.80 (471878 hom.)
• Consequence: ACACB NM_001093.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• Publications: 12 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 -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACACB	NM_001093.4	c.6046-28A>G		intron_variant	Intron 43 of 52	ENST00000338432.12	NP_001084.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACACB	ENST00000338432.12	c.6046-28A>G		intron_variant	Intron 43 of 52	1	NM_001093.4	ENSP00000341044.7
ACACB	ENST00000377848.7	c.6046-28A>G		intron_variant	Intron 42 of 51	1		ENSP00000367079.3
ACACB	ENST00000377854.9	c.2044-28A>G		intron_variant	Intron 42 of 46	5		ENSP00000367085.6
ACACB	ENST00000538526.5	n.2044-28A>G		intron_variant	Intron 15 of 25	5		ENSP00000443281.1

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117252 AN: 151832 Hom.: 45753 Cov.: 30

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.728

Gnomad AMR AF: 0.839

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.782

GnomAD2 exomes AF: 0.793 AC: 198749 AN: 250766 AF XY: 0.789

Gnomad AFR exome AF: 0.662

Gnomad AMR exome AF: 0.879

Gnomad ASJ exome AF: 0.822

Gnomad EAS exome AF: 0.699

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.816

Gnomad OTH exome AF: 0.808

GnomAD4 exome AF: 0.803 AC: 1171198 AN: 1459234 Hom.: 471878 Cov.: 38 AF XY: 0.799 AC XY: 579886 AN XY: 726080

African (AFR) AF: 0.662 AC: 22089 AN: 33356

American (AMR) AF: 0.875 AC: 39087 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 21465 AN: 26108

East Asian (EAS) AF: 0.698 AC: 27661 AN: 39652

South Asian (SAS) AF: 0.675 AC: 58127 AN: 86090

European-Finnish (FIN) AF: 0.857 AC: 45774 AN: 53388

Middle Eastern (MID) AF: 0.786 AC: 4529 AN: 5764

European-Non Finnish (NFE) AF: 0.815 AC: 904925 AN: 1109950

Other (OTH) AF: 0.789 AC: 47541 AN: 60280

GnomAD4 genome AF: 0.772 AC: 117293 AN: 151950 Hom.: 45756 Cov.: 30 AF XY: 0.773 AC XY: 57436 AN XY: 74292

African (AFR) AF: 0.668 AC: 27649 AN: 41402

American (AMR) AF: 0.839 AC: 12811 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2906 AN: 3472

East Asian (EAS) AF: 0.691 AC: 3556 AN: 5146

South Asian (SAS) AF: 0.659 AC: 3172 AN: 4810

European-Finnish (FIN) AF: 0.860 AC: 9088 AN: 10566

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

European-Non Finnish (NFE) AF: 0.817 AC: 55552 AN: 67962

Other (OTH) AF: 0.781 AC: 1647 AN: 2108

Alfa AF: 0.805 Hom.: 64646

Bravo AF: 0.768

Asia WGS AF: 0.701 AC: 2438 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		0.087
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2075259; hg19: chr12-109691991;