Variant 1-119750771-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005518.4(HMGCS2):c.*5+26G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,467,736 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 37 hom., cov: 32)

Exomes 𝑓: 0.016 ( 210 hom. )

Consequence

HMGCS2
NM_005518.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.19

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 1-119750771-C-G is Benign according to our data. Variant chr1-119750771-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1187245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0172 (2617/152236) while in subpopulation AFR AF= 0.0257 (1066/41534). AF 95% confidence interval is 0.0244. There are 37 homozygotes in gnomad4. There are 1181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4 linkuse as main transcript	c.*5+26G>C		intron_variant		ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1 linkuse as main transcript	c.*5+26G>C		intron_variant			NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8 linkuse as main transcript	c.*5+26G>C		intron_variant		1	NM_005518.4	ENSP00000358414	P1	P54868-1
HMGCS2	ENST00000544913.2 linkuse as main transcript	c.*5+26G>C		intron_variant		2		ENSP00000439495		P54868-2

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2610

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0256

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00913

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0125

AC:

3126

AN:

250084

Hom.:

AF XY:

0.0124

AC XY:

1677

AN XY:

135148

show subpopulations

Gnomad AFR exome

AF:

0.0238

Gnomad AMR exome

AF:

0.00937

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.000654

Gnomad SAS exome

AF:

0.00966

Gnomad FIN exome

AF:

0.00584

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.0157

AC:

20704

AN:

1315500

Hom.:

210

Cov.:

AF XY:

0.0154

AC XY:

10182

AN XY:

662632

show subpopulations

Gnomad4 AFR exome

AF:

0.0258

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.000198

Gnomad4 EAS exome

AF:

0.000257

Gnomad4 SAS exome

AF:

0.00922

Gnomad4 FIN exome

AF:

0.00623

Gnomad4 NFE exome

AF:

0.0179

Gnomad4 OTH exome

AF:

0.0141

GnomAD4 genome

AF:

0.0172

AC:

2617

AN:

152236

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1181

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0257

Gnomad4 AMR

AF:

0.0138

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00893

Gnomad4 FIN

AF:

0.00490

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0129

Hom.:

Bravo

AF:

0.0185

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

8.6

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over