2-190205025-G-C

Variant names:

• chr2-190205025-G-C
• rs114799177
• NM_014362.4:c.*92C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014362.4(HIBCH):​c.*92C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 726,598 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (10 hom.)
• Consequence: HIBCH NM_014362.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.373
• Publications: 0 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: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), 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=-0.86).
• BP6: Variant 2-190205025-G-C is Benign according to our data. Variant chr2-190205025-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1321705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1595/152238) while in subpopulation AFR AF = 0.0368 (1528/41536). AF 95% confidence interval is 0.0353. There are 22 homozygotes in GnomAd4. There are 772 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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.*92C>G		3_prime_UTR	Exon 14 of 14	NP_055177.2
	HIBCH	NM_198047.3		c.*202C>G		3_prime_UTR	Exon 13 of 13	NP_932164.1	Q6NVY1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIBCH	ENST00000359678.10	TSL:1 MANE Select	c.*92C>G		3_prime_UTR	Exon 14 of 14	ENSP00000352706.5	Q6NVY1-1
	HIBCH	ENST00000392332.7	TSL:1	c.*202C>G		3_prime_UTR	Exon 13 of 13	ENSP00000376144.3	Q6NVY1-2
	HIBCH	ENST00000870408.1		c.*92C>G		3_prime_UTR	Exon 14 of 14	ENSP00000540467.1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1588 AN: 152122 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00131 AC: 752 AN: 574360 Hom.: 10 Cov.: 6 AF XY: 0.00102 AC XY: 316 AN XY: 310160

African (AFR) AF: 0.0353 AC: 565 AN: 16018

American (AMR) AF: 0.00183 AC: 64 AN: 35024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20108

East Asian (EAS) AF: 0.00 AC: 0 AN: 32512

South Asian (SAS) AF: 0.000111 AC: 7 AN: 63044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48212

Middle Eastern (MID) AF: 0.00244 AC: 6 AN: 2460

European-Non Finnish (NFE) AF: 0.0000399 AC: 13 AN: 326138

Other (OTH) AF: 0.00314 AC: 97 AN: 30844

GnomAD4 genome AF: 0.0105 AC: 1595 AN: 152238 Hom.: 22 Cov.: 32 AF XY: 0.0104 AC XY: 772 AN XY: 74446

African (AFR) AF: 0.0368 AC: 1528 AN: 41536

American (AMR) AF: 0.00288 AC: 44 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67996

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00777 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely 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	-0.86
CADD	Benign	2.3
DANN	Benign	0.37
PhyloP100		0.37
PromoterAI		0.013	Neutral
Mutation Taster		=100/0	polymorphism

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: rs114799177; hg19: chr2-191069751;