chr11-72293429-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030813.6(CLPB):​c.2062A>G​(p.Lys688Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CLPB
NM_030813.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.18
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11965707).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CLPBNM_030813.6 linkuse as main transcriptc.2062A>G p.Lys688Glu missense_variant 17/17 ENST00000294053.9
CLPBNM_001258392.3 linkuse as main transcriptc.1972A>G p.Lys658Glu missense_variant 16/16 ENST00000538039.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CLPBENST00000294053.9 linkuse as main transcriptc.2062A>G p.Lys688Glu missense_variant 17/171 NM_030813.6 P4Q9H078-1
CLPBENST00000538039.6 linkuse as main transcriptc.1972A>G p.Lys658Glu missense_variant 16/162 NM_001258392.3 A1Q9H078-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 23, 2023This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 688 of the CLPB protein (p.Lys688Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CLPB-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.082
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.052
T;.;.;T;.;.
Eigen
Benign
-0.16
Eigen_PC
Benign
0.0010
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.82
T;T;T;T;T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.12
T;T;T;T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
1.9
L;.;.;.;.;.
MutationTaster
Benign
0.73
N;N;N;N;N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.1
N;N;N;N;N;.
REVEL
Benign
0.046
Sift
Benign
0.051
T;D;T;D;T;.
Sift4G
Benign
0.21
T;T;T;T;T;.
Polyphen
0.17
B;.;B;.;.;.
Vest4
0.18
MutPred
0.31
Loss of MoRF binding (P = 0.0018);.;.;.;.;.;
MVP
0.56
MPC
0.61
ClinPred
0.41
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-72004473; API