HMGCS2 p.Ser286Arg

Variant names:

• chr1-119757433-T-G
• NM_005518.4:c.856A>C
• HMGCS2 p.Ser286Arg

Your query was ambiguous. Multiple possible variants found:

• chr1-119757433-T-G
• chr1-119757431-G-T
• chr1-119757431-G-C
• chr1-119757431-GCT-ACG
• chr1-119757431-GCT-TCG
• chr1-119757431-GCT-CCG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005518.4(HMGCS2):​c.856A>C​(p.Ser286Arg) 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 benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S286S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HMGCS2 NM_005518.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 0 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16592672).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005518.4. 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
	HMGCS2	NM_005518.4	MANE Select	c.856A>C	p.Ser286Arg	missense	Exon 5 of 10	NP_005509.1	P54868-1
	HMGCS2	NM_001166107.1		c.730A>C	p.Ser244Arg	missense	Exon 4 of 9	NP_001159579.1	P54868-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	ENST00000369406.8	TSL:1 MANE Select	c.856A>C	p.Ser286Arg	missense	Exon 5 of 10	ENSP00000358414.3	P54868-1
	HMGCS2	ENST00000886233.1		c.883A>C	p.Ser295Arg	missense	Exon 6 of 11	ENSP00000556292.1
	HMGCS2	ENST00000886228.1		c.856A>C	p.Ser286Arg	missense	Exon 5 of 10	ENSP00000556287.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.9
DANN	Benign	0.67
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.11
Sift	Benign	0.43	T
Sift4G	Benign	0.50	T
Varity_R		0.23
gMVP		0.37
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-120300056;