NM_005518.4:c.*5+68A>G

Variant names:

• chr1-119750729-T-C
• rs667226
• NM_005518.4:c.*5+68A>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+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
• 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=-0.89).
• BP6: Variant 1-119750729-T-C is Benign according to our data. Variant chr1-119750729-T-C is described in ClinVar as Benign. ClinVar VariationId 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.

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+68A>G		intron	N/A	NP_005509.1	P54868-1
	HMGCS2	NM_001166107.1		c.*5+68A>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+68A>G		intron	N/A	ENSP00000358414.3	P54868-1
	HMGCS2	ENST00000886236.1		c.*73A>G		3_prime_UTR	Exon 9 of 9	ENSP00000556295.1
	HMGCS2	ENST00000886233.1		c.*5+68A>G		intron	N/A	ENSP00000556292.1

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

African (AFR) AF: 0.0677 AC: 1449 AN: 21418

American (AMR) AF: 0.0815 AC: 3333 AN: 40872

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3156 AN: 22040

East Asian (EAS) AF: 0.140 AC: 5092 AN: 36358

South Asian (SAS) AF: 0.157 AC: 11189 AN: 71476

European-Finnish (FIN) AF: 0.107 AC: 5534 AN: 51924

Middle Eastern (MID) AF: 0.250 AC: 1144 AN: 4572

European-Non Finnish (NFE) AF: 0.160 AC: 86918 AN: 544898

Other (OTH) AF: 0.142 AC: 5656 AN: 39894

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

African (AFR) AF: 0.0661 AC: 2748 AN: 41548

American (AMR) AF: 0.103 AC: 1572 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 486 AN: 3472

East Asian (EAS) AF: 0.122 AC: 629 AN: 5172

South Asian (SAS) AF: 0.139 AC: 671 AN: 4812

European-Finnish (FIN) AF: 0.107 AC: 1136 AN: 10592

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10722 AN: 67996

Other (OTH) AF: 0.150 AC: 316 AN: 2112

Alfa AF: 0.148 Hom.: 3727

Bravo AF: 0.119

Asia WGS AF: 0.127 AC: 440 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	-0.89
CADD	Benign	2.5
DANN	Benign	0.74
PhyloP100		1.1
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: rs667226; hg19: chr1-120293352; COSMIC: COSV65569177; COSMIC: COSV65569177;