chr11-72293408-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030813.6(CLPB):​c.2083C>T​(p.Arg695Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,614,144 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R695P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

CLPB
NM_030813.6 missense

Scores

3
4
11

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.55
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005453825).
BP6
Variant 11-72293408-G-A is Benign according to our data. Variant chr11-72293408-G-A is described in ClinVar as [Benign]. Clinvar id is 542779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72293408-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00302 (460/152282) while in subpopulation AFR AF= 0.0107 (444/41566). AF 95% confidence interval is 0.00986. There are 5 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CLPBNM_030813.6 linkuse as main transcriptc.2083C>T p.Arg695Trp missense_variant 17/17 ENST00000294053.9
CLPBNM_001258392.3 linkuse as main transcriptc.1993C>T p.Arg665Trp missense_variant 16/16 ENST00000538039.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CLPBENST00000294053.9 linkuse as main transcriptc.2083C>T p.Arg695Trp missense_variant 17/171 NM_030813.6 P4Q9H078-1
CLPBENST00000538039.6 linkuse as main transcriptc.1993C>T p.Arg665Trp missense_variant 16/162 NM_001258392.3 A1Q9H078-2

Frequencies

GnomAD3 genomes
AF:
0.00302
AC:
460
AN:
152164
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0107
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000736
AC:
185
AN:
251380
Hom.:
1
AF XY:
0.000537
AC XY:
73
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.0105
Gnomad AMR exome
AF:
0.000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000306
AC:
447
AN:
1461862
Hom.:
1
Cov.:
31
AF XY:
0.000261
AC XY:
190
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0116
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.000497
GnomAD4 genome
AF:
0.00302
AC:
460
AN:
152282
Hom.:
5
Cov.:
32
AF XY:
0.00314
AC XY:
234
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0107
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.000575
Hom.:
1
Bravo
AF:
0.00345
ESP6500AA
AF:
0.00977
AC:
43
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00101
AC:
122
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxMar 27, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2022CLPB: BP4, BS1, BS2 -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
CLPB-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 07, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
3-methylglutaconic aciduria, type VIIB Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.074
T;.;.;T;.;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D
MetaRNN
Benign
0.0055
T;T;T;T;T;T
MetaSVM
Benign
-0.55
T
MutationAssessor
Benign
1.8
L;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-2.0
N;N;N;N;N;.
REVEL
Benign
0.14
Sift
Pathogenic
0.0
D;D;D;D;D;.
Sift4G
Uncertain
0.0020
D;D;D;D;D;.
Polyphen
1.0
D;.;D;.;.;.
Vest4
0.30
MVP
0.78
MPC
0.91
ClinPred
0.096
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.64

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141383303; hg19: chr11-72004452; API