chr1-119750546-T-C

Position:

• chr1-119750546-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005518.4(HMGCS2):​c.*5+251A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0832 in 152,246 control chromosomes in the GnomAD database, including 717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.083 (717 hom., cov: 32)
• Consequence: HMGCS2 NM_005518.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.829

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-119750546-T-C is Benign according to our data. Variant chr1-119750546-T-C is described in ClinVar as [Benign]. Clinvar id is 1282669.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.*5+251A>G		intron_variant		ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.*5+251A>G		intron_variant			NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.*5+251A>G		intron_variant		1	NM_005518.4	ENSP00000358414	P1
HMGCS2	ENST00000544913.2	c.*5+251A>G		intron_variant		2		ENSP00000439495

Frequencies

GnomAD3 genomes AF: 0.0831 AC: 12647 AN: 152128 Hom.: 712 Cov.: 32

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.0937

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0819

Gnomad OTH AF: 0.110

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0832 AC: 12661 AN: 152246 Hom.: 717 Cov.: 32 AF XY: 0.0839 AC XY: 6245 AN XY: 74440

Gnomad4 AFR AF: 0.0522

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.0417

Gnomad4 SAS AF: 0.0934

Gnomad4 FIN AF: 0.0420

Gnomad4 NFE AF: 0.0819

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0870 Hom.: 941

Bravo AF: 0.0925

Asia WGS AF: 0.0790 AC: 274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.73

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

LitVar

Other links and lift over

dbSNP: rs2241868; hg19: chr1-120293169;