rs2300455

Variant names:

• chr12-109185711-G-A
• rs2300455
• NM_001093.4:c.1951G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-109185711-G-A
• chr12-109185711-G-C
• chr12-109185711-G-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.1951G>A​(p.Ala651Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,610,442 control chromosomes in the GnomAD database, including 29,893 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 0.15 (2121 hom., cov: 31)
  • Exomes 𝑓: 0.19 (27772 hom.)
• Consequence: ACACB NM_001093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.13
• Publications: 34 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=0.0026296377).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.266 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.1951G>A	p.Ala651Thr	missense	Exon 12 of 53	NP_001084.3	O00763-1
	ACACB	NM_001412734.1		c.1951G>A	p.Ala651Thr	missense	Exon 13 of 54	NP_001399663.1	O00763-1
	ACACB	NM_001412735.1		c.1951G>A	p.Ala651Thr	missense	Exon 12 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.1951G>A	p.Ala651Thr	missense	Exon 12 of 53	ENSP00000341044.7	O00763-1
	ACACB	ENST00000377848.7	TSL:1	c.1951G>A	p.Ala651Thr	missense	Exon 11 of 52	ENSP00000367079.3	O00763-1
	ACACB	ENST00000377854.9	TSL:5	c.-2052G>A		5_prime_UTR	Exon 11 of 47	ENSP00000367085.6	F8W8T8

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22893 AN: 151788 Hom.: 2119 Cov.: 31

Gnomad AFR AF: 0.0389

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.189 AC: 47034 AN: 248896 AF XY: 0.193

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.275

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.192 AC: 280110 AN: 1458536 Hom.: 27772 Cov.: 33 AF XY: 0.193 AC XY: 140255 AN XY: 725190

African (AFR) AF: 0.0309 AC: 1031 AN: 33326

American (AMR) AF: 0.164 AC: 7309 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5528 AN: 26084

East Asian (EAS) AF: 0.269 AC: 10618 AN: 39418

South Asian (SAS) AF: 0.224 AC: 19226 AN: 85896

European-Finnish (FIN) AF: 0.169 AC: 9014 AN: 53384

Middle Eastern (MID) AF: 0.138 AC: 795 AN: 5760

European-Non Finnish (NFE) AF: 0.194 AC: 215317 AN: 1109934

Other (OTH) AF: 0.187 AC: 11272 AN: 60278

GnomAD4 genome AF: 0.151 AC: 22893 AN: 151906 Hom.: 2121 Cov.: 31 AF XY: 0.152 AC XY: 11256 AN XY: 74174

African (AFR) AF: 0.0388 AC: 1610 AN: 41458

American (AMR) AF: 0.165 AC: 2524 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 730 AN: 3468

East Asian (EAS) AF: 0.278 AC: 1420 AN: 5108

South Asian (SAS) AF: 0.228 AC: 1094 AN: 4808

European-Finnish (FIN) AF: 0.168 AC: 1772 AN: 10550

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13172 AN: 67958

Other (OTH) AF: 0.157 AC: 330 AN: 2096

Alfa AF: 0.178 Hom.: 9268

Bravo AF: 0.143

TwinsUK AF: 0.203 AC: 754

ALSPAC AF: 0.202 AC: 777

ESP6500AA AF: 0.0449 AC: 198

ESP6500EA AF: 0.198 AC: 1704

ExAC AF: 0.189 AC: 22901

Asia WGS AF: 0.239 AC: 830 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Benign	0.052	T
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.19
MPC		0.48
ClinPred		0.018	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.72
Mutation Taster		=98/2	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: rs2300455; hg19: chr12-109623516; COSMIC: COSV58131773;