rs2075260

Variant names:

• chr12-109259033-G-A
• rs2075260
• NM_001093.4:c.6421G>A

Variant summary

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

The NM_001093.4(ACACB):​c.6421G>A​(p.Val2141Ile) variant causes a missense change. The variant allele was found at a frequency of 0.802 in 1,613,858 control chromosomes in the GnomAD database, including 520,681 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.78 (47107 hom., cov: 31)
  • Exomes 𝑓: 0.80 (473574 hom.)
• Consequence: ACACB NM_001093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.14
• Publications: 38 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: Computational evidence support a benign effect (MetaRNN=6.803952E-7).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.834 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	NM_001093.4	MANE Select	c.6421G>A	p.Val2141Ile	missense	Exon 47 of 53	NP_001084.3	O00763-1
	ACACB	NM_001412734.1		c.6421G>A	p.Val2141Ile	missense	Exon 48 of 54	NP_001399663.1	O00763-1
	ACACB	NM_001412735.1		c.6421G>A	p.Val2141Ile	missense	Exon 47 of 53	NP_001399664.1	O00763-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	ENST00000338432.12	TSL:1 MANE Select	c.6421G>A	p.Val2141Ile	missense	Exon 47 of 53	ENSP00000341044.7	O00763-1
	ACACB	ENST00000377848.7	TSL:1	c.6421G>A	p.Val2141Ile	missense	Exon 46 of 52	ENSP00000367079.3	O00763-1
	ACACB	ENST00000377854.9	TSL:5	c.2419G>A	p.Val807Ile	missense	Exon 46 of 47	ENSP00000367085.6	F8W8T8

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119286 AN: 151938 Hom.: 47088 Cov.: 31

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.839

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.852

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.816

Gnomad OTH AF: 0.796

GnomAD2 exomes AF: 0.797 AC: 200465 AN: 251372 AF XY: 0.792

Gnomad AFR exome AF: 0.707

Gnomad AMR exome AF: 0.883

Gnomad ASJ exome AF: 0.822

Gnomad EAS exome AF: 0.746

Gnomad FIN exome AF: 0.851

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.809

GnomAD4 exome AF: 0.804 AC: 1174914 AN: 1461802 Hom.: 473574 Cov.: 58 AF XY: 0.800 AC XY: 581547 AN XY: 727204

African (AFR) AF: 0.709 AC: 23725 AN: 33474

American (AMR) AF: 0.879 AC: 39295 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 21496 AN: 26136

East Asian (EAS) AF: 0.751 AC: 29795 AN: 39688

South Asian (SAS) AF: 0.673 AC: 58044 AN: 86244

European-Finnish (FIN) AF: 0.848 AC: 45311 AN: 53416

Middle Eastern (MID) AF: 0.798 AC: 4601 AN: 5768

European-Non Finnish (NFE) AF: 0.814 AC: 904843 AN: 1111962

Other (OTH) AF: 0.792 AC: 47804 AN: 60394

GnomAD4 genome AF: 0.785 AC: 119353 AN: 152056 Hom.: 47107 Cov.: 31 AF XY: 0.786 AC XY: 58438 AN XY: 74340

African (AFR) AF: 0.710 AC: 29436 AN: 41446

American (AMR) AF: 0.846 AC: 12932 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.839 AC: 2910 AN: 3470

East Asian (EAS) AF: 0.739 AC: 3813 AN: 5160

South Asian (SAS) AF: 0.657 AC: 3166 AN: 4818

European-Finnish (FIN) AF: 0.852 AC: 9017 AN: 10588

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

European-Non Finnish (NFE) AF: 0.816 AC: 55499 AN: 67974

Other (OTH) AF: 0.793 AC: 1670 AN: 2106

Alfa AF: 0.796 Hom.: 82170

Bravo AF: 0.784

TwinsUK AF: 0.814 AC: 3020

ALSPAC AF: 0.817 AC: 3147

ESP6500AA AF: 0.711 AC: 3133

ESP6500EA AF: 0.817 AC: 7025

ExAC AF: 0.789 AC: 95791

Asia WGS AF: 0.714 AC: 2484 AN: 3478

EpiCase AF: 0.811

EpiControl AF: 0.810

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	6.8e-7	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-3.5	N
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.93	N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.027
MPC		0.19
ClinPred		0.015	T
GERP RS		5.1
Varity_R		0.040
gMVP		0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2075260; hg19: chr12-109696838; COSMIC: COSV58129739; COSMIC: COSV58129739;