rs886041120

Positions:

• chr11-72293446-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000294053.9(CLPB):​c.2045T>A​(p.Ile682Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLPB ENST00000294053.9 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.08

Genes affected

CLPB (HGNC:30664): (ClpB family mitochondrial disaggregase) This gene belongs to the ATP-ases associated with diverse cellular activities (AAA+) superfamily. Members of this superfamily form ring-shaped homo-hexamers and have highly conserved ATPase domains that are involved in various processes including DNA replication, protein degradation and reactivation of misfolded proteins. All members of this family hydrolyze ATP through their AAA+ domains and use the energy generated through ATP hydrolysis to exert mechanical force on their substrates. In addition to an AAA+ domain, the protein encoded by this gene contains a C-terminal D2 domain, which is characteristic of the AAA+ subfamily of Caseinolytic peptidases to which this protein belongs. It cooperates with Hsp70 in the disaggregation of protein aggregates. Allelic variants of this gene are associated with 3-methylglutaconic aciduria, which causes cataracts and neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLPB	NM_030813.6	c.2045T>A	p.Ile682Asn	missense_variant	17/17	ENST00000294053.9	NP_110440.1
CLPB	NM_001258392.3	c.1955T>A	p.Ile652Asn	missense_variant	16/16	ENST00000538039.6	NP_001245321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9	c.2045T>A	p.Ile682Asn	missense_variant	17/17	1	NM_030813.6	ENSP00000294053	P4
CLPB	ENST00000538039.6	c.1955T>A	p.Ile652Asn	missense_variant	16/16	2	NM_001258392.3	ENSP00000441518	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	L;.;.;.;.;.
MutationTaster	Benign	0.95	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.
Polyphen		0.97	D;.;P;.;.;.
Vest4		0.71
MutPred		0.21		Loss of helix (P = 0.0017);.;.;.;.;.;
MVP		0.72
MPC		1.4
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.77
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs886041120; hg19: chr11-72004490;