rs1992376

Variant names:

• chr1-119757431-G-A
• rs1992376
• NM_005518.4:c.858C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-119757431-G-A
• chr1-119757431-G-C
• chr1-119757431-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005518.4(HMGCS2):​c.858C>T​(p.Ser286Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 1,613,814 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (62 hom.)
• Consequence: HMGCS2 NM_005518.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.95
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-119757431-G-A is Benign according to our data. Variant chr1-119757431-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00526 (801/152254) while in subpopulation NFE AF = 0.00897 (610/68012). AF 95% confidence interval is 0.00838. There are 2 homozygotes in GnomAd4. There are 360 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.858C>T	p.Ser286Ser	synonymous	Exon 5 of 10	NP_005509.1	P54868-1
	HMGCS2	NM_001166107.1		c.732C>T	p.Ser244Ser	synonymous	Exon 4 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.858C>T	p.Ser286Ser	synonymous	Exon 5 of 10	ENSP00000358414.3	P54868-1
	HMGCS2	ENST00000886233.1		c.885C>T	p.Ser295Ser	synonymous	Exon 6 of 11	ENSP00000556292.1
	HMGCS2	ENST00000886228.1		c.858C>T	p.Ser286Ser	synonymous	Exon 5 of 10	ENSP00000556287.1

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 801 AN: 152136 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00897

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00511 AC: 1282 AN: 251084 AF XY: 0.00512

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00614

Gnomad NFE exome AF: 0.00802

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00815 AC: 11908 AN: 1461560 Hom.: 62 Cov.: 32 AF XY: 0.00797 AC XY: 5793 AN XY: 727108

African (AFR) AF: 0.00108 AC: 36 AN: 33472

American (AMR) AF: 0.00177 AC: 79 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 168 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00185 AC: 160 AN: 86256

European-Finnish (FIN) AF: 0.00681 AC: 364 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00968 AC: 10756 AN: 1111708

Other (OTH) AF: 0.00558 AC: 337 AN: 60376

GnomAD4 genome AF: 0.00526 AC: 801 AN: 152254 Hom.: 2 Cov.: 33 AF XY: 0.00484 AC XY: 360 AN XY: 74446

African (AFR) AF: 0.00178 AC: 74 AN: 41524

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00897 AC: 610 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00735 Hom.: 3

Bravo AF: 0.00470

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.47
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1992376; hg19: chr1-120300054; COSMIC: COSV65568979;