1-119750744-T-C

Variant names:

• chr1-119750744-T-C
• rs667246
• NM_005518.4:c.*5+53A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005518.4(HMGCS2):​c.*5+53A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 1,134,288 control chromosomes in the GnomAD database, including 267,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34579 hom., cov: 32)
  • Exomes 𝑓: 0.69 (233054 hom.)
• Consequence: HMGCS2 NM_005518.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.438
• Publications: 6 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-119750744-T-C is Benign according to our data. Variant chr1-119750744-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

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.*5+53A>G		intron	N/A	NP_005509.1	P54868-1
	HMGCS2	NM_001166107.1		c.*5+53A>G		intron	N/A	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.*5+53A>G		intron	N/A	ENSP00000358414.3	P54868-1
	HMGCS2	ENST00000886236.1		c.*58A>G		3_prime_UTR	Exon 9 of 9	ENSP00000556295.1
	HMGCS2	ENST00000886233.1		c.*5+53A>G		intron	N/A	ENSP00000556292.1

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102185 AN: 151862 Hom.: 34545 Cov.: 32

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.708

GnomAD4 exome AF: 0.687 AC: 674501 AN: 982308 Hom.: 233054 AF XY: 0.693 AC XY: 352574 AN XY: 508876

African (AFR) AF: 0.645 AC: 15604 AN: 24208

American (AMR) AF: 0.689 AC: 29533 AN: 42856

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 18252 AN: 23078

East Asian (EAS) AF: 0.620 AC: 23123 AN: 37272

South Asian (SAS) AF: 0.797 AC: 60206 AN: 75530

European-Finnish (FIN) AF: 0.600 AC: 31572 AN: 52582

Middle Eastern (MID) AF: 0.832 AC: 4040 AN: 4858

European-Non Finnish (NFE) AF: 0.682 AC: 461597 AN: 677208

Other (OTH) AF: 0.684 AC: 30574 AN: 44716

GnomAD4 genome AF: 0.673 AC: 102264 AN: 151980 Hom.: 34579 Cov.: 32 AF XY: 0.673 AC XY: 50012 AN XY: 74262

African (AFR) AF: 0.645 AC: 26753 AN: 41454

American (AMR) AF: 0.723 AC: 11053 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2723 AN: 3472

East Asian (EAS) AF: 0.630 AC: 3252 AN: 5162

South Asian (SAS) AF: 0.791 AC: 3803 AN: 4808

European-Finnish (FIN) AF: 0.600 AC: 6318 AN: 10524

Middle Eastern (MID) AF: 0.829 AC: 242 AN: 292

European-Non Finnish (NFE) AF: 0.678 AC: 46091 AN: 67964

Other (OTH) AF: 0.702 AC: 1481 AN: 2110

Alfa AF: 0.693 Hom.: 47607

Bravo AF: 0.680

Asia WGS AF: 0.676 AC: 2353 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.4
DANN	Benign	0.50
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

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: rs667246; hg19: chr1-120293367; COSMIC: COSV65569024; COSMIC: COSV65569024;