12-109191652-C-T

Variant names:

• chr12-109191652-C-T
• rs7135947
• NM_001093.4:c.2184C>T

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.2184C>T​(p.Gly728Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,613,776 control chromosomes in the GnomAD database, including 213,475 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 0.45 (16637 hom., cov: 32)
  • Exomes 𝑓: 0.51 (196838 hom.)
• Consequence: ACACB NM_001093.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 23 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=-0.71).
• BP7: Synonymous conserved (PhyloP=-2.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 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.2184C>T	p.Gly728Gly	synonymous	Exon 14 of 53	NP_001084.3
	ACACB	NM_001412734.1		c.2184C>T	p.Gly728Gly	synonymous	Exon 15 of 54	NP_001399663.1
	ACACB	NM_001412735.1		c.2184C>T	p.Gly728Gly	synonymous	Exon 14 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.2184C>T	p.Gly728Gly	synonymous	Exon 14 of 53	ENSP00000341044.7
	ACACB	ENST00000377848.7	TSL:1	c.2184C>T	p.Gly728Gly	synonymous	Exon 13 of 52	ENSP00000367079.3
	ACACB	ENST00000544651.1	TSL:3	n.175C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68266 AN: 151904 Hom.: 16640 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.701

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.503

GnomAD2 exomes AF: 0.493 AC: 123965 AN: 251404 AF XY: 0.498

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.545

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.535

GnomAD4 exome AF: 0.515 AC: 752291 AN: 1461754 Hom.: 196838 Cov.: 54 AF XY: 0.515 AC XY: 374210 AN XY: 727180

African (AFR) AF: 0.248 AC: 8295 AN: 33480

American (AMR) AF: 0.549 AC: 24565 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 14807 AN: 26132

East Asian (EAS) AF: 0.256 AC: 10174 AN: 39698

South Asian (SAS) AF: 0.451 AC: 38893 AN: 86254

European-Finnish (FIN) AF: 0.521 AC: 27818 AN: 53404

Middle Eastern (MID) AF: 0.611 AC: 3522 AN: 5766

European-Non Finnish (NFE) AF: 0.534 AC: 593930 AN: 1111912

Other (OTH) AF: 0.502 AC: 30287 AN: 60390

GnomAD4 genome AF: 0.449 AC: 68275 AN: 152022 Hom.: 16637 Cov.: 32 AF XY: 0.449 AC XY: 33328 AN XY: 74302

African (AFR) AF: 0.258 AC: 10702 AN: 41454

American (AMR) AF: 0.519 AC: 7927 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1984 AN: 3470

East Asian (EAS) AF: 0.265 AC: 1369 AN: 5170

South Asian (SAS) AF: 0.432 AC: 2074 AN: 4806

European-Finnish (FIN) AF: 0.524 AC: 5542 AN: 10580

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36789 AN: 67956

Other (OTH) AF: 0.500 AC: 1054 AN: 2108

Alfa AF: 0.511 Hom.: 84191

Bravo AF: 0.442

Asia WGS AF: 0.370 AC: 1284 AN: 3476

EpiCase AF: 0.562

EpiControl AF: 0.559

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.15
DANN	Benign	0.72
PhyloP100		-2.3
Mutation Taster		=78/22	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: rs7135947; hg19: chr12-109629457; COSMIC: COSV58130613;