1-119757427-G-T

Variant names:

• chr1-119757427-G-T
• rs142637231
• NM_005518.4:c.862C>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.862C>A​(p.Arg288Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 1,613,770 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: HMGCS2 NM_005518.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.641
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-119757427-G-T is Benign according to our data. Variant chr1-119757427-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.641 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00242 (369/152248) while in subpopulation AFR AF = 0.00852 (354/41526). AF 95% confidence interval is 0.00779. There are 2 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.862C>A	p.Arg288Arg	synonymous	Exon 5 of 10	NP_005509.1	P54868-1
	HMGCS2	NM_001166107.1		c.736C>A	p.Arg246Arg	synonymous	Exon 4 of 9	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.862C>A	p.Arg288Arg	synonymous	Exon 5 of 10	ENSP00000358414.3	P54868-1
	HMGCS2	ENST00000886233.1		c.889C>A	p.Arg297Arg	synonymous	Exon 6 of 11	ENSP00000556292.1
	HMGCS2	ENST00000886228.1		c.862C>A	p.Arg288Arg	synonymous	Exon 5 of 10	ENSP00000556287.1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152130 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000613 AC: 154 AN: 251136 AF XY: 0.000449

Gnomad AFR exome AF: 0.00904

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000265 AC: 388 AN: 1461522 Hom.: 3 Cov.: 32 AF XY: 0.000234 AC XY: 170 AN XY: 727106

African (AFR) AF: 0.00977 AC: 327 AN: 33466

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111672

Other (OTH) AF: 0.000596 AC: 36 AN: 60388

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152248 Hom.: 2 Cov.: 33 AF XY: 0.00227 AC XY: 169 AN XY: 74442

African (AFR) AF: 0.00852 AC: 354 AN: 41526

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00231 Hom.: 4

Bravo AF: 0.00279

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	3-hydroxy-3-methylglutaryl-CoA synthase deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.8
DANN	Benign	0.49
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs142637231; hg19: chr1-120300050;