1-119764384-C-G

Variant names:

• chr1-119764384-C-G
• NM_005518.4:c.347G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005518.4(HMGCS2):​c.347G>C​(p.Arg116Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R116C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HMGCS2 NM_005518.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.347G>C	p.Arg116Pro	missense_variant	Exon 2 of 10	ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.347G>C	p.Arg116Pro	missense_variant	Exon 2 of 9		NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.347G>C	p.Arg116Pro	missense_variant	Exon 2 of 10	1	NM_005518.4	ENSP00000358414.3
HMGCS2	ENST00000544913.2	c.347G>C	p.Arg116Pro	missense_variant	Exon 2 of 9	2		ENSP00000439495.2
HMGCS2	ENST00000476640.1	n.243G>C		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.61		Loss of MoRF binding (P = 0.0559);Loss of MoRF binding (P = 0.0559);
MVP		0.96
MPC		0.59
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.94
gMVP		0.90

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-120307007;