2-190246167-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014362.4(HIBCH):c.796G>A(p.Asp266Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,581,178 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D266D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 17 hom. )

Consequence

HIBCH
NM_014362.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.52

Publications

5 publications found

Variant links:

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

HIBCH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0078730285).

BP6

Variant 2-190246167-C-T is Benign according to our data. Variant chr2-190246167-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235593.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00298 (453/152236) while in subpopulation NFE AF = 0.00554 (377/68000). AF 95% confidence interval is 0.00508. There are 2 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIBCH	NM_014362.4 link	c.796G>A	p.Asp266Asn	missense_variant	Exon 10 of 14	ENST00000359678.10	NP_055177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIBCH	ENST00000359678.10 link	c.796G>A	p.Asp266Asn	missense_variant	Exon 10 of 14	1	NM_014362.4	ENSP00000352706.5

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

453

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00554

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00253

AC:

632

AN:

249884

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.00487

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.00438

AC:

6261

AN:

1428942

Hom.:

Cov.:

AF XY:

0.00424

AC XY:

3025

AN XY:

713134

show subpopulations

African (AFR)

AF:

0.000761

AC:

AN:

32832

American (AMR)

AF:

0.000493

AC:

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.000154

AC:

AN:

25908

East Asian (EAS)

AF:

0.00

AC:

AN:

39378

South Asian (SAS)

AF:

0.000702

AC:

AN:

85524

European-Finnish (FIN)

AF:

0.000488

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5304

European-Non Finnish (NFE)

AF:

0.00544

AC:

5888

AN:

1082968

Other (OTH)

AF:

0.00399

AC:

236

AN:

59150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

251

501

752

1002

1253

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00298

AC:

453

AN:

152236

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41556

American (AMR)

AF:

0.000589

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000755

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00554

AC:

377

AN:

68000

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00309

Hom.:

Bravo

AF:

0.00288

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00524

AC:

ExAC

AF:

0.00250

AC:

303

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00507

EpiControl

AF:

0.00469

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HIBCH: BP4, BS2 -

Jun 12, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

3-hydroxyisobutyryl-CoA hydrolase deficiency

Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

HIBCH-related disorder

Benign:1

Mar 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

.;T;D;D;.

Eigen

Benign

0.034

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.0079

T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.8

L;L;.;.;.

PhyloP100

2.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.3

N;N;N;N;N

REVEL

Benign

0.096

Sift

Benign

0.18

T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;.

Polyphen

0.0

B;B;.;.;.

Vest4

0.38

MVP

0.67

MPC

0.034

ClinPred

0.020

GERP RS

4.0

PromoterAI

0.0042

Neutral

(source)

Varity_R

0.28

gMVP

0.27

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over