chr11-72294645-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

The NM_030813.6(CLPB):c.1625A>T(p.Glu542Val) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,184 control chromosomes in the GnomAD database, including 39 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. E542K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 38 hom. )

Consequence

CLPB
NM_030813.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.99

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

3-methylglutaconic aciduria, type VIIB
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
neutropenia, severe congenital, 9, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

CLPB links:

ENSG00000255843 (HGNC:):

ENSG00000255843 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 11-72294645-T-A is Benign according to our data. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72294645-T-A is described in CliVar as Benign. Clinvar id is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000656 (100/152372) while in subpopulation SAS AF = 0.0192 (93/4834). AF 95% confidence interval is 0.0161. There are 1 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 38 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPB	NM_030813.6 link	c.1625A>T	p.Glu542Val	missense_variant	Exon 14 of 17	ENST00000294053.9	NP_110440.1	Q9H078-1A0A140VK11
CLPB	NM_001258392.3 link	c.1535A>T	p.Glu512Val	missense_variant	Exon 13 of 16	ENST00000538039.6	NP_001245321.1	Q9H078-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9 link	c.1625A>T	p.Glu542Val	missense_variant	Exon 14 of 17	1	NM_030813.6	ENSP00000294053.3		Q9H078-1
CLPB	ENST00000538039.6 link	c.1535A>T	p.Glu512Val	missense_variant	Exon 13 of 16	2	NM_001258392.3	ENSP00000441518.1		Q9H078-2

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

101

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0194

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00242

AC:

608

AN:

251450

AF XY:

0.00327

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00122

AC:

1777

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1273

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0186

AC:

1603

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000827

AC:

AN:

1111944

Other (OTH)

AF:

0.00126

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000656

AC:

100

AN:

152372

Hom.:

Cov.:

AF XY:

0.000939

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41582

American (AMR)

AF:

0.000196

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0192

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.00270

AC:

328

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

3-methylglutaconic aciduria, type VIIB

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.;D;.;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D

MetaRNN

Benign

0.0072

T;T;T;T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.4

M;.;.;.;.;.;.

PhyloP100

5.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.0

D;D;D;D;D;.;.

REVEL

Uncertain

0.37

Sift

Uncertain

0.0050

D;D;D;D;D;.;.

Sift4G

Uncertain

0.0060

D;D;D;D;D;.;.

Polyphen

1.0

D;.;P;.;.;.;.

Vest4

0.60

MutPred

0.52

Gain of MoRF binding (P = 0.028);.;.;.;.;.;.;

MVP

0.51

MPC

1.2

ClinPred

0.078

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.86

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.87

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over