11-72293408-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 Likely 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

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

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]

CLPB links:

Genome browser will be placed here

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 [Likely_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 GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_030813.6 linkuse as main transcript	c.2083C>T	p.Arg695Trp	missense_variant	17/17	ENST00000294053.9
CLPB	NM_001258392.3 linkuse as main transcript	c.1993C>T	p.Arg665Trp	missense_variant	16/16	ENST00000538039.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9 linkuse as main transcript	c.2083C>T	p.Arg695Trp	missense_variant	17/17	1	NM_030813.6	P4	Q9H078-1
CLPB	ENST00000538039.6 linkuse as main transcript	c.1993C>T	p.Arg665Trp	missense_variant	16/16	2	NM_001258392.3	A1	Q9H078-2

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

460

AN:

152164

Hom.:

Cov.:

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.:

AF XY:

0.000537

AC XY:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00345

ESP6500AA

AF:

0.00977

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00101

AC:

122

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2018	This 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 submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	CLPB: BP4, BS1, BS2 -

CLPB-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2020

This 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 submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.074

T;.;.;T;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

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

MutationAssessor

Benign

1.8

L;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.21

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over