rs2229312

Variant names:

• chr15-40413026-C-T
• rs2229312
• NM_002225.5:c.723C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002225.5(IVD):​c.723C>T​(p.Asp241Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,612,232 control chromosomes in the GnomAD database, including 13,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1152 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12518 hom.)
• Consequence: IVD NM_002225.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.461

Genes affected

IVD (HGNC:6186): (isovaleryl-CoA dehydrogenase) Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism. The genetic deficiency of IVD results in an accumulation of isovaleric acid, which is toxic to the central nervous system and leads to isovaleric acidemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 15-40413026-C-T is Benign according to our data. Variant chr15-40413026-C-T is described in ClinVar as [Benign]. Clinvar id is 94057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40413026-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.461 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IVD	NM_002225.5	c.723C>T	p.Asp241Asp	synonymous_variant	Exon 7 of 12	ENST00000487418.8	NP_002216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IVD	ENST00000487418.8	c.723C>T	p.Asp241Asp	synonymous_variant	Exon 7 of 12	1	NM_002225.5	ENSP00000418397.3

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17579 AN: 152138 Hom.: 1152 Cov.: 33

Gnomad AFR AF: 0.0828

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0965

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.0998

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.115 AC: 28885 AN: 251426 Hom.: 1998 AF XY: 0.117 AC XY: 15945 AN XY: 135884

Gnomad AFR exome AF: 0.0838

Gnomad AMR exome AF: 0.0604

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0125

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.127 AC: 185480 AN: 1459976 Hom.: 12518 Cov.: 32 AF XY: 0.127 AC XY: 92034 AN XY: 726384

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.0623

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.00962

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.116 AC: 17586 AN: 152256 Hom.: 1152 Cov.: 33 AF XY: 0.118 AC XY: 8783 AN XY: 74440

Gnomad4 AFR AF: 0.0828

Gnomad4 AMR AF: 0.0964

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.0133

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.113

Alfa AF: 0.126 Hom.: 669

Bravo AF: 0.103

Asia WGS AF: 0.0630 AC: 220 AN: 3478

EpiCase AF: 0.126

EpiControl AF: 0.132

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isovaleryl-CoA dehydrogenase deficiency Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2229312; hg19: chr15-40705225;