1-119750729-T-C

Position:

• chr1-119750729-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005518.4(HMGCS2):​c.*5+68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 985,656 control chromosomes in the GnomAD database, including 10,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1291 hom., cov: 32)
  • Exomes 𝑓: 0.15 (9697 hom.)
• Consequence: HMGCS2 NM_005518.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-119750729-T-C is Benign according to our data. Variant chr1-119750729-T-C is described in ClinVar as [Benign]. Clinvar id is 1292120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.*5+68A>G		intron_variant		ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.*5+68A>G		intron_variant			NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.*5+68A>G		intron_variant		1	NM_005518.4	ENSP00000358414	P1
HMGCS2	ENST00000544913.2	c.*5+68A>G		intron_variant		2		ENSP00000439495

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18454 AN: 152086 Hom.: 1291 Cov.: 32

Gnomad AFR AF: 0.0661

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.148 AC: 123471 AN: 833452 Hom.: 9697 AF XY: 0.150 AC XY: 65710 AN XY: 437468

Gnomad4 AFR exome AF: 0.0677

Gnomad4 AMR exome AF: 0.0815

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.121 AC: 18459 AN: 152204 Hom.: 1291 Cov.: 32 AF XY: 0.119 AC XY: 8870 AN XY: 74416

Gnomad4 AFR AF: 0.0661

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.150

Alfa AF: 0.155 Hom.: 1250

Bravo AF: 0.119

Asia WGS AF: 0.127 AC: 440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.5
DANN	Benign	0.74

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

LitVar

Other links and lift over

dbSNP: rs667226; hg19: chr1-120293352; COSMIC: COSV65569177; COSMIC: COSV65569177;