NM_033261.3:c.627G>C

Variant names:

• chr10-1019574-C-G
• rs138894690
• NM_033261.3:c.627G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_033261.3(IDI2):​c.627G>C​(p.Trp209Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IDI2 NM_033261.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63
• Publications: 0 publications found

Genes affected

IDI2 (HGNC:23487): (isopentenyl-diphosphate delta isomerase 2) The protein encoded by this gene catalyzes the conversion of isopentenyl diphosphate to dimethylallyl diphosphate, which is a precursor for the synthesis of cholesterol and other isoprenoids. This gene, which is a product of an ancestral gene duplication event, encodes a protein that may be involved in the aggregation of alpha-synuclein in the cerebral cortex of patients with Lewy body disease. In addition, segmental copy number gains in this locus have been associated with sporadic amyotrophic lateral sclerosis. [provided by RefSeq, Jul 2016]

GTPBP4 (HGNC:21535): (GTP binding protein 4) GTP-binding proteins are GTPases and function as molecular switches that can flip between two states: active, when GTP is bound, and inactive, when GDP is bound. 'Active' in this context usually means that the molecule acts as a signal to trigger other events in the cell. When an extracellular ligand binds to a G-protein-linked receptor, the receptor changes its conformation and switches on the trimeric G proteins that associate with it by causing them to eject their GDP and replace it with GTP. The switch is turned off when the G protein hydrolyzes its own bound GTP, converting it back to GDP. But before that occurs, the active protein has an opportunity to diffuse away from the receptor and deliver its message for a prolonged period to its downstream target. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033261.3. 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
	IDI2	NM_033261.3	MANE Select	c.627G>C	p.Trp209Cys	missense	Exon 5 of 5	NP_150286.1	Q9BXS1
	GTPBP4	NM_012341.3	MANE Select	c.*2347C>G		3_prime_UTR	Exon 17 of 17	NP_036473.2	Q9BZE4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDI2	ENST00000277517.2	TSL:1 MANE Select	c.627G>C	p.Trp209Cys	missense	Exon 5 of 5	ENSP00000277517.1	Q9BXS1
	GTPBP4	ENST00000360803.9	TSL:1 MANE Select	c.*2347C>G		3_prime_UTR	Exon 17 of 17	ENSP00000354040.4	Q9BZE4-1
	IDI2	ENST00000955306.1		c.627G>C	p.Trp209Cys	missense	Exon 6 of 6	ENSP00000625365.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.87		Loss of MoRF binding (P = 0.0279)
MVP		0.60
MPC		0.19
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.96
gMVP		0.89
Mutation Taster		=31/69	disease causing

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: rs138894690; hg19: chr10-1065514;