2-190252480-G-A

Variant names:

• chr2-190252480-G-A
• rs291402
• NM_014362.4:c.518-173C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014362.4(HIBCH):​c.518-173C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 152,048 control chromosomes in the GnomAD database, including 8,364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.31 (8364 hom., cov: 32)
• Consequence: HIBCH NM_014362.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00200
• Publications: 4 publications found

Genes affected

HIBCH (HGNC:4908): (3-hydroxyisobutyryl-CoA hydrolase) This gene encodes the enzyme responsible for hydrolysis of both HIBYL-CoA and beta-hydroxypropionyl-CoA. Mutations in this gene have been associated with 3-hyroxyisobutyryl-CoA hydrolase deficiency. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

HIBCH Gene-Disease associations (from GenCC):

• 3-hydroxyisobutyryl-CoA hydrolase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-190252480-G-A is Benign according to our data. Variant chr2-190252480-G-A is described in ClinVar as Benign. ClinVar VariationId is 1251709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014362.4. 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
	HIBCH	NM_014362.4	MANE Select	c.518-173C>T		intron	N/A	NP_055177.2
	HIBCH	NM_198047.3		c.518-173C>T		intron	N/A	NP_932164.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIBCH	ENST00000359678.10	TSL:1 MANE Select	c.518-173C>T		intron	N/A	ENSP00000352706.5
	HIBCH	ENST00000392332.7	TSL:1	c.518-173C>T		intron	N/A	ENSP00000376144.3
	HIBCH	ENST00000870406.1		c.518-173C>T		intron	N/A	ENSP00000540465.1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 47014 AN: 151930 Hom.: 8327 Cov.: 32

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.321

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

GnomAD4 genome AF: 0.310 AC: 47105 AN: 152048 Hom.: 8364 Cov.: 32 AF XY: 0.305 AC XY: 22649 AN XY: 74352

African (AFR) AF: 0.465 AC: 19267 AN: 41422

American (AMR) AF: 0.282 AC: 4319 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3472

East Asian (EAS) AF: 0.455 AC: 2355 AN: 5174

South Asian (SAS) AF: 0.248 AC: 1196 AN: 4824

European-Finnish (FIN) AF: 0.132 AC: 1402 AN: 10592

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16855 AN: 67958

Other (OTH) AF: 0.324 AC: 683 AN: 2108

Alfa AF: 0.272 Hom.: 778

Bravo AF: 0.330

Asia WGS AF: 0.353 AC: 1222 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.38
PhyloP100		-0.0020
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: rs291402; hg19: chr2-191117206;