1-119752550-C-T

Variant names:

• chr1-119752550-C-T
• rs142776952
• NM_005518.4:c.1419G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005518.4(HMGCS2):​c.1419G>A​(p.Lys473Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,613,912 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (138 hom.)
• Consequence: HMGCS2 NM_005518.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002780
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.290
• Publications: 3 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-119752550-C-T is Benign according to our data. Variant chr1-119752550-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00345 (525/152258) while in subpopulation SAS AF = 0.0386 (186/4816). AF 95% confidence interval is 0.0341. There are 11 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.1419G>A	p.Lys473Lys	splice_region synonymous	Exon 8 of 10	NP_005509.1
	HMGCS2	NM_001166107.1		c.1293G>A	p.Lys431Lys	splice_region synonymous	Exon 7 of 9	NP_001159579.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	ENST00000369406.8	TSL:1 MANE Select	c.1419G>A	p.Lys473Lys	splice_region synonymous	Exon 8 of 10	ENSP00000358414.3
	HMGCS2	ENST00000886233.1		c.1446G>A	p.Lys482Lys	splice_region synonymous	Exon 9 of 11	ENSP00000556292.1
	HMGCS2	ENST00000886228.1		c.1419G>A	p.Lys473Lys	splice_region synonymous	Exon 8 of 10	ENSP00000556287.1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152140 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0388

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00797 AC: 2004 AN: 251474 AF XY: 0.0101

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00513 AC: 7503 AN: 1461654 Hom.: 138 Cov.: 32 AF XY: 0.00646 AC XY: 4694 AN XY: 727112

African (AFR) AF: 0.00108 AC: 36 AN: 33478

American (AMR) AF: 0.00295 AC: 132 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0442 AC: 3810 AN: 86236

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53394

Middle Eastern (MID) AF: 0.0413 AC: 238 AN: 5764

European-Non Finnish (NFE) AF: 0.00246 AC: 2739 AN: 1111868

Other (OTH) AF: 0.00573 AC: 346 AN: 60376

GnomAD4 genome AF: 0.00345 AC: 525 AN: 152258 Hom.: 11 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74448

African (AFR) AF: 0.000602 AC: 25 AN: 41550

American (AMR) AF: 0.00334 AC: 51 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0386 AC: 186 AN: 4816

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00390 Hom.: 9

Bravo AF: 0.00247

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00486

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	3-hydroxy-3-methylglutaryl-CoA synthase deficiency (4)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.7
DANN	Benign	0.78
PhyloP100		-0.29
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.10
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: rs142776952; hg19: chr1-120295173;