rs1992376

Positions:

• chr1-119757431-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005518.4(HMGCS2):​c.858C>T​(p.Ser286=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 1,613,814 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (62 hom.)
• Consequence: HMGCS2 NM_005518.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.95

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-119757431-G-A is Benign according to our data. Variant chr1-119757431-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 292334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00526 (801/152254) while in subpopulation NFE AF= 0.00897 (610/68012). AF 95% confidence interval is 0.00838. There are 2 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCS2	NM_005518.4	c.858C>T	p.Ser286=	synonymous_variant	5/10	ENST00000369406.8
HMGCS2	NM_001166107.1	c.732C>T	p.Ser244=	synonymous_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCS2	ENST00000369406.8	c.858C>T	p.Ser286=	synonymous_variant	5/10	1	NM_005518.4	P1
HMGCS2	ENST00000544913.2	c.732C>T	p.Ser244=	synonymous_variant	4/9	2
HMGCS2	ENST00000472375.5	n.305C>T		non_coding_transcript_exon_variant	2/3	5
HMGCS2	ENST00000476640.1	n.589C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 801 AN: 152136 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00897

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00511 AC: 1282 AN: 251084 Hom.: 9 AF XY: 0.00512 AC XY: 695 AN XY: 135688

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00614

Gnomad NFE exome AF: 0.00802

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00815 AC: 11908 AN: 1461560 Hom.: 62 Cov.: 32 AF XY: 0.00797 AC XY: 5793 AN XY: 727108

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00185

Gnomad4 FIN exome AF: 0.00681

Gnomad4 NFE exome AF: 0.00968

Gnomad4 OTH exome AF: 0.00558

GnomAD4 genome AF: 0.00526 AC: 801 AN: 152254 Hom.: 2 Cov.: 33 AF XY: 0.00484 AC XY: 360 AN XY: 74446

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.00897

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00761 Hom.: 2

Bravo AF: 0.00470

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-hydroxy-3-methylglutaryl-CoA synthase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	HMGCS2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1992376; hg19: chr1-120300054; COSMIC: COSV65568979;