1-119753304-G-C

Variant names:

• chr1-119753304-G-C
• rs137852637
• NM_005518.4:c.1270C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_005518.4(HMGCS2):​c.1270C>G​(p.Arg424Gly) variant causes a missense change involving the alteration of a non-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. R424Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMGCS2 NM_005518.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985
• Publications: 7 publications found

Genes affected

HMGCS2 (HGNC:5008): (3-hydroxy-3-methylglutaryl-CoA synthase 2) The protein encoded by this gene belongs to the HMG-CoA synthase family. It is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting. Mutations in this gene are associated with HMG-CoA synthase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

HMGCS2 Gene-Disease associations (from GenCC):

• 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.19124 (below the threshold of 3.09). Trascript score misZ: 0.52753 (below the threshold of 3.09). GenCC associations: The gene is linked to 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.1270C>G	p.Arg424Gly	missense_variant	Exon 7 of 10	ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.1144C>G	p.Arg382Gly	missense_variant	Exon 6 of 9		NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.1270C>G	p.Arg424Gly	missense_variant	Exon 7 of 10	1	NM_005518.4	ENSP00000358414.3
HMGCS2	ENST00000544913.2	c.1144C>G	p.Arg382Gly	missense_variant	Exon 6 of 9	2		ENSP00000439495.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Benign	-0.0036
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.92	D;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.6	H;.
PhyloP100		0.98
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.93	P;.
Vest4		0.67
MutPred		0.72		Gain of catalytic residue at V425 (P = 0.0169);.;
MVP		0.82
MPC		0.35
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.67
gMVP		0.63
Mutation Taster		=66/34	polymorphism

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: rs137852637; hg19: chr1-120295927;