rs2229312

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

IVD Gene-Disease associations (from GenCC):

• isovaleric acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.104).
• BP6: Variant 15-40413026-C-T is Benign according to our data. Variant chr15-40413026-C-T is described in ClinVar as Benign. ClinVar VariationId is 94057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002225.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	NM_002225.5	MANE Select	c.723C>T	p.Asp241Asp	synonymous	Exon 7 of 12	NP_002216.3
	IVD	NM_001354601.3		c.723C>T	p.Asp241Asp	synonymous	Exon 7 of 12	NP_001341530.2
	IVD	NM_001354600.3		c.810C>T	p.Asp270Asp	synonymous	Exon 7 of 13	NP_001341529.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IVD	ENST00000487418.8	TSL:1 MANE Select	c.723C>T	p.Asp241Asp	synonymous	Exon 7 of 12	ENSP00000418397.3
	IVD	ENST00000479013.7	TSL:1	c.633C>T	p.Asp211Asp	synonymous	Exon 6 of 11	ENSP00000417990.3
	IVD	ENST00000651168.1		c.732C>T	p.Asp244Asp	synonymous	Exon 7 of 12	ENSP00000499074.1

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

GnomAD2 exomes AF: 0.115 AC: 28885 AN: 251426 AF XY: 0.117

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 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

African (AFR) AF: 0.0813 AC: 2720 AN: 33456

American (AMR) AF: 0.0623 AC: 2786 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3668 AN: 26126

East Asian (EAS) AF: 0.00962 AC: 382 AN: 39696

South Asian (SAS) AF: 0.100 AC: 8636 AN: 86228

European-Finnish (FIN) AF: 0.207 AC: 11070 AN: 53400

Middle Eastern (MID) AF: 0.112 AC: 640 AN: 5736

European-Non Finnish (NFE) AF: 0.133 AC: 147862 AN: 1110288

Other (OTH) AF: 0.128 AC: 7716 AN: 60324

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

African (AFR) AF: 0.0828 AC: 3440 AN: 41542

American (AMR) AF: 0.0964 AC: 1475 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 520 AN: 3472

East Asian (EAS) AF: 0.0133 AC: 69 AN: 5184

South Asian (SAS) AF: 0.100 AC: 483 AN: 4826

European-Finnish (FIN) AF: 0.215 AC: 2277 AN: 10596

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8978 AN: 68008

Other (OTH) AF: 0.113 AC: 239 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Isovaleryl-CoA dehydrogenase deficiency (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.58
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229312; hg19: chr15-40705225; COSMIC: COSV108020739; COSMIC: COSV108020739;