12-109185711-G-C

Position:

• chr12-109185711-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001093.4(ACACB):​c.1951G>C​(p.Ala651Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A651T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACACB NM_001093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.13

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACACB	NM_001093.4	c.1951G>C	p.Ala651Pro	missense_variant	12/53	ENST00000338432.12	NP_001084.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACACB	ENST00000338432.12	c.1951G>C	p.Ala651Pro	missense_variant	12/53	1	NM_001093.4	ENSP00000341044.7
ACACB	ENST00000377848.7	c.1951G>C	p.Ala651Pro	missense_variant	11/52	1		ENSP00000367079.3
ACACB	ENST00000377854	c.-2052G>C		5_prime_UTR_variant	11/47	5		ENSP00000367085.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.80		Gain of catalytic residue at R652 (P = 0.0013);Gain of catalytic residue at R652 (P = 0.0013);
MVP		0.65
MPC		0.99
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2300455; hg19: chr12-109623516;