NM_005518.4:c.104+1496T>C

Variant names:

• chr1-119767245-A-G
• rs3790692
• NM_005518.4:c.104+1496T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005518.4(HMGCS2):​c.104+1496T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 152,038 control chromosomes in the GnomAD database, including 9,882 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (9882 hom., cov: 32)
• Consequence: HMGCS2 NM_005518.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	NM_005518.4	MANE Select	c.104+1496T>C		intron	N/A	NP_005509.1
	HMGCS2	NM_001166107.1		c.104+1496T>C		intron	N/A	NP_001159579.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	ENST00000369406.8	TSL:1 MANE Select	c.104+1496T>C		intron	N/A	ENSP00000358414.3
	HMGCS2	ENST00000544913.2	TSL:2	c.104+1496T>C		intron	N/A	ENSP00000439495.2

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53500 AN: 151920 Hom.: 9866 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.335

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

GnomAD4 genome AF: 0.352 AC: 53549 AN: 152038 Hom.: 9882 Cov.: 32 AF XY: 0.352 AC XY: 26139 AN XY: 74328

African (AFR) AF: 0.239 AC: 9898 AN: 41464

American (AMR) AF: 0.336 AC: 5131 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1336 AN: 3464

East Asian (EAS) AF: 0.362 AC: 1865 AN: 5154

South Asian (SAS) AF: 0.269 AC: 1296 AN: 4818

European-Finnish (FIN) AF: 0.470 AC: 4966 AN: 10564

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27808 AN: 67968

Other (OTH) AF: 0.336 AC: 711 AN: 2116

Alfa AF: 0.383 Hom.: 22996

Bravo AF: 0.338

Asia WGS AF: 0.346 AC: 1203 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.7
DANN	Benign	0.44
PhyloP100		-0.037
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3790692; hg19: chr1-120309868;