rs76773981

Variant names:

• chr1-119750807-C-T
• rs76773981
• NM_005518.4:c.1522G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-119750807-C-T
• chr1-119750807-C-A
• chr1-119750807-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_005518.4(HMGCS2):​c.1522G>A​(p.Val508Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,611,352 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (6 hom.)
• Consequence: HMGCS2 NM_005518.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.18
• Publications: 5 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 -10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005518.4
• 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=0.0043078065).
• BP6: Variant 1-119750807-C-T is Benign according to our data. Variant chr1-119750807-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 292327.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00229 (349/152212) while in subpopulation NFE AF = 0.00382 (260/68014). AF 95% confidence interval is 0.00344. There are 1 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1522G>A	p.Val508Ile	missense	Exon 9 of 10	NP_005509.1	P54868-1
	HMGCS2	NM_001166107.1		c.1396G>A	p.Val466Ile	missense	Exon 8 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.1522G>A	p.Val508Ile	missense	Exon 9 of 10	ENSP00000358414.3	P54868-1
	HMGCS2	ENST00000886233.1		c.1549G>A	p.Val517Ile	missense	Exon 10 of 11	ENSP00000556292.1
	HMGCS2	ENST00000886228.1		c.1522G>A	p.Val508Ile	missense	Exon 9 of 10	ENSP00000556287.1

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152094 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00188 AC: 472 AN: 251182 AF XY: 0.00189

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00295 AC: 4310 AN: 1459140 Hom.: 6 Cov.: 31 AF XY: 0.00294 AC XY: 2134 AN XY: 726118

African (AFR) AF: 0.000359 AC: 12 AN: 33386

American (AMR) AF: 0.000693 AC: 31 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00735 AC: 192 AN: 26106

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86196

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00345 AC: 3824 AN: 1109604

Other (OTH) AF: 0.00360 AC: 217 AN: 60306

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74422

African (AFR) AF: 0.000770 AC: 32 AN: 41532

American (AMR) AF: 0.000458 AC: 7 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00382 AC: 260 AN: 68014

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00302 Hom.: 2

Bravo AF: 0.00218

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00181 AC: 220

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	3-hydroxy-3-methylglutaryl-CoA synthase deficiency (2)
-	-	1	HMGCS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.27
DANN	Benign	0.77
DEOGEN2	Benign	0.13	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.10
Sift	Benign	0.38	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.33
MPC		0.081
ClinPred		0.0043	T
GERP RS		-7.8
Varity_R		0.036
gMVP		0.074
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs76773981; hg19: chr1-120293430;