17-37252940-C-G

Variant names:

• chr17-37252940-C-G
• rs2229416
• NM_198834.3:c.1923G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198834.3(ACACA):​c.1923G>C​(p.Gln641His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q641Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACACA NM_198834.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.09
• Publications: 23 publications found

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]

ACACA Gene-Disease associations (from GenCC):

• acetyl-coa carboxylase deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198834.3. 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
	ACACA	NM_198834.3	MANE Select	c.1923G>C	p.Gln641His	missense	Exon 15 of 56	NP_942131.1	Q13085-4
	ACACA	NM_198836.3		c.1812G>C	p.Gln604His	missense	Exon 15 of 56	NP_942133.1	Q13085-1
	ACACA	NM_198839.3		c.1812G>C	p.Gln604His	missense	Exon 19 of 60	NP_942136.1	Q13085-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACA	ENST00000616317.5	TSL:1 MANE Select	c.1923G>C	p.Gln641His	missense	Exon 15 of 56	ENSP00000483300.1	Q13085-4
	ACACA	ENST00000614428.4	TSL:1	c.1812G>C	p.Gln604His	missense	Exon 15 of 56	ENSP00000478547.1	Q13085-1
	ACACA	ENST00000613146.4	TSL:1	n.2008G>C		non_coding_transcript_exon	Exon 15 of 29

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.65	N
PhyloP100		4.1
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.037	D
Polyphen		0.95	P
Vest4		0.37
MutPred		0.47		Gain of helix (P = 0.132)
MVP		0.47
ClinPred		0.82	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.89

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: rs2229416; hg19: chr17-35609866;