rs143097446

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030813.6(CLPB):c.668G>A(p.Ser223Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,614,066 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 53 hom. )

Consequence

CLPB
NM_030813.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.22

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041360855).

BP6

Variant 11-72372993-C-T is Benign according to our data. Variant chr11-72372993-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00445 (677/152248) while in subpopulation NFE AF = 0.00739 (503/68022). AF 95% confidence interval is 0.00686. There are 3 homozygotes in GnomAd4. There are 305 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPB	NM_030813.6 link	c.668G>A	p.Ser223Asn	missense_variant	Exon 5 of 17	ENST00000294053.9	NP_110440.1	Q9H078-1A0A140VK11
CLPB	NM_001258392.3 link	c.646+7288G>A		intron_variant	Intron 4 of 15	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.668G>A	p.Ser223Asn	missense_variant	Exon 5 of 17	1	NM_030813.6	ENSP00000294053.3		Q9H078-1
CLPB	ENST00000538039.6 link	c.646+7288G>A		intron_variant	Intron 4 of 15	2	NM_001258392.3	ENSP00000441518.1		Q9H078-2

Frequencies

GnomAD3 genomes

AF:

0.00445

AC:

677

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00739

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00461

AC:

1157

AN:

251248

AF XY:

0.00450

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00702

Gnomad NFE exome

AF:

0.00778

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00707

AC:

10328

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00684

AC XY:

4976

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

33480

American (AMR)

AF:

0.00177

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00590

AC:

315

AN:

53412

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00860

AC:

9568

AN:

1111950

Other (OTH)

AF:

0.00474

AC:

286

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

510

1020

1529

2039

2549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

380

760

1140

1520

1900

<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:

0.00445

AC:

677

AN:

152248

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

305

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41536

American (AMR)

AF:

0.00262

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00739

AC:

503

AN:

68022

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

122

153

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:

0.00603

Hom.:

Bravo

AF:

0.00423

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00676

AC:

ExAC

AF:

0.00451

AC:

548

EpiCase

AF:

0.00692

EpiControl

AF:

0.00782

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24439111) -

Apr 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLPB: BP4, BS2 -

not specified

Benign:1

Oct 27, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

3-methylglutaconic aciduria, type VIIB;C5676954:Neutropenia, severe congenital, 9, autosomal dominant;C5676967:3-methylglutaconic aciduria, type VIIA

Benign:1

Jul 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

3-methylglutaconic aciduria, type VIIB

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.028

T;.;T;.;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.70

T;T;T;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.0041

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.;.;.;.;.

PhyloP100

1.2

PROVEAN

Benign

-0.20

N;N;N;.;N;.

REVEL

Benign

0.018

Sift

Benign

0.037

D;D;D;.;T;.

Sift4G

Benign

0.23

T;T;T;.;T;.

Polyphen

0.019

B;.;.;.;.;.

Vest4

0.35

MVP

0.54

MPC

0.36

ClinPred

0.0048

GERP RS

2.2

Varity_R

0.051

gMVP

0.37

Mutation Taster

=95/5

polymorphism

(source)

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

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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