rs1992376

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005518.4(HMGCS2):​c.858C>T​(p.Ser286Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 1,613,814 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0081 ( 62 hom. )

Consequence

HMGCS2
NM_005518.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.95

Publications

2 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 1-119757431-G-A is Benign according to our data. Variant chr1-119757431-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.95 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00526 (801/152254) while in subpopulation NFE AF = 0.00897 (610/68012). AF 95% confidence interval is 0.00838. There are 2 homozygotes in GnomAd4. There are 360 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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HMGCS2NM_005518.4 linkc.858C>T p.Ser286Ser synonymous_variant Exon 5 of 10 ENST00000369406.8 NP_005509.1 P54868-1A0A140VJL2
HMGCS2NM_001166107.1 linkc.732C>T p.Ser244Ser synonymous_variant Exon 4 of 9 NP_001159579.1 P54868-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HMGCS2ENST00000369406.8 linkc.858C>T p.Ser286Ser synonymous_variant Exon 5 of 10 1 NM_005518.4 ENSP00000358414.3 P54868-1
HMGCS2ENST00000544913.2 linkc.732C>T p.Ser244Ser synonymous_variant Exon 4 of 9 2 ENSP00000439495.2 P54868-2
HMGCS2ENST00000472375.5 linkn.305C>T non_coding_transcript_exon_variant Exon 2 of 3 5
HMGCS2ENST00000476640.1 linkn.589C>T non_coding_transcript_exon_variant Exon 3 of 4 3

Frequencies

GnomAD3 genomes
AF:
0.00527
AC:
801
AN:
152136
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00179
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00216
Gnomad ASJ
AF:
0.00519
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000830
Gnomad FIN
AF:
0.00518
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00897
Gnomad OTH
AF:
0.00287
GnomAD2 exomes
AF:
0.00511
AC:
1282
AN:
251084
AF XY:
0.00512
show subpopulations
Gnomad AFR exome
AF:
0.00154
Gnomad AMR exome
AF:
0.00173
Gnomad ASJ exome
AF:
0.00596
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00614
Gnomad NFE exome
AF:
0.00802
Gnomad OTH exome
AF:
0.00555
GnomAD4 exome
AF:
0.00815
AC:
11908
AN:
1461560
Hom.:
62
Cov.:
32
AF XY:
0.00797
AC XY:
5793
AN XY:
727108
show subpopulations
African (AFR)
AF:
0.00108
AC:
36
AN:
33472
American (AMR)
AF:
0.00177
AC:
79
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00643
AC:
168
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00185
AC:
160
AN:
86256
European-Finnish (FIN)
AF:
0.00681
AC:
364
AN:
53420
Middle Eastern (MID)
AF:
0.00139
AC:
8
AN:
5768
European-Non Finnish (NFE)
AF:
0.00968
AC:
10756
AN:
1111708
Other (OTH)
AF:
0.00558
AC:
337
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
658
1316
1974
2632
3290
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
402
804
1206
1608
2010
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00526
AC:
801
AN:
152254
Hom.:
2
Cov.:
33
AF XY:
0.00484
AC XY:
360
AN XY:
74446
show subpopulations
African (AFR)
AF:
0.00178
AC:
74
AN:
41524
American (AMR)
AF:
0.00216
AC:
33
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00519
AC:
18
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.000830
AC:
4
AN:
4818
European-Finnish (FIN)
AF:
0.00518
AC:
55
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00897
AC:
610
AN:
68012
Other (OTH)
AF:
0.00284
AC:
6
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
36
71
107
142
178
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00735
Hom.:
3
Bravo
AF:
0.00470
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

3-hydroxy-3-methylglutaryl-CoA synthase deficiency Benign:3
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 03, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2
Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

HMGCS2: BP4, BP7, BS2 -

not specified Benign:1
Jan 05, 2017
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
2.6
DANN
Benign
0.47
PhyloP100
-1.9
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1992376; hg19: chr1-120300054; COSMIC: COSV65568979; API