chr17-37097984-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_198834.3(ACACA):c.6566G>A(p.Gly2189Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000181 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
ACACA
NM_198834.3 missense, splice_region
NM_198834.3 missense, splice_region
Scores
1
5
7
Splicing: ADA: 0.9986
2
Clinical Significance
Conservation
PhyloP100: 4.92
Genes affected
ACACA (HGNC:84): (acetyl-CoA carboxylase alpha) 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. There are two ACC forms, alpha and beta, encoded by two different genes. ACC-alpha is highly enriched in lipogenic tissues. The enzyme is under long term control at the transcriptional and translational levels and under short term regulation by the phosphorylation/dephosphorylation of targeted serine residues and by allosteric transformation by citrate or palmitoyl-CoA. Multiple alternatively spliced transcript variants divergent in the 5' sequence and encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, ACACA
BS2
?
High AC in GnomAd at 20 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACACA | NM_198834.3 | c.6566G>A | p.Gly2189Glu | missense_variant, splice_region_variant | 53/56 | ENST00000616317.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACACA | ENST00000616317.5 | c.6566G>A | p.Gly2189Glu | missense_variant, splice_region_variant | 53/56 | 1 | NM_198834.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000322 AC: 81AN: 251454Hom.: 0 AF XY: 0.000331 AC XY: 45AN XY: 135898
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GnomAD4 exome AF: 0.000186 AC: 272AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.000182 AC XY: 132AN XY: 727246
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2022 | The c.6455G>A (p.G2152E) alteration is located in exon 57 (coding exon 51) of the ACACA gene. This alteration results from a G to A substitution at nucleotide position 6455, causing the glycine (G) at amino acid position 2152 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2021 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ACACA-related conditions. This variant is present in population databases (rs199873625, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2152 of the ACACA protein (p.Gly2152Glu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T;T;T
Polyphen
D;B;B;.;.
Vest4
MVP
ClinPred
T
GERP RS
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gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at