Genetic Variant HMGCS2:p.Ser375Cys (chr1-119755490-G-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_005518.4(HMGCS2):c.1124C>G(p.Ser375Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,614,138 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 20 hom. )

Consequence

HMGCS2
NM_005518.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 9.40

Publications

1 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

HMGCS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.19124 (below the threshold of 3.09). Trascript score misZ: 0.52753 (below the threshold of 3.09). GenCC associations: The gene is linked to 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.013461292).

BP6

Variant 1-119755490-G-C is Benign according to our data. Variant chr1-119755490-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000643 (98/152294) while in subpopulation SAS AF = 0.0141 (68/4818). AF 95% confidence interval is 0.0114. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 20 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.1124C>G	p.Ser375Cys	missense	Exon 6 of 10	NP_005509.1	P54868-1
	HMGCS2	NM_001166107.1		c.998C>G	p.Ser333Cys	missense	Exon 5 of 9	NP_001159579.1	P54868-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGCS2	ENST00000369406.8	TSL:1 MANE Select	c.1124C>G	p.Ser375Cys	missense	Exon 6 of 10	ENSP00000358414.3	P54868-1
HMGCS2	ENST00000886233.1		c.1151C>G	p.Ser384Cys	missense	Exon 7 of 11	ENSP00000556292.1
HMGCS2	ENST00000886228.1		c.1124C>G	p.Ser375Cys	missense	Exon 6 of 10	ENSP00000556287.1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00181

AC:

454

AN:

251486

AF XY:

0.00230

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000325

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000968

AC:

1415

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

968

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0128

AC:

1108

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000194

AC:

216

AN:

1111966

Other (OTH)

AF:

0.00104

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

189

283

378

472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000643

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41558

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0141

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68034

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000402

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00189

AC:

230

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-hydroxy-3-methylglutaryl-CoA synthase deficiency (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.076

MutationAssessor

Uncertain

2.2

PhyloP100

9.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.58

Sift

Uncertain

0.011

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.86

MVP

0.91

MPC

0.51

ClinPred

0.062

GERP RS

5.6

Varity_R

0.63

gMVP

0.47

Mutation Taster

=87/13

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over