rs7938203

chr11-72329786-C-Gchr11-72329786-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030813.6(CLPB):c.884G>C(p.Arg295Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,613,810 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R295R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (91 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (95 hom.)
• Consequence: CLPB NM_030813.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.25

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002591908).
• BP6: Variant 11-72329786-C-G is Benign according to our data. Variant chr11-72329786-C-G is described in ClinVar as [Benign]. Clinvar id is 380518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_030813.6	c.884G>C	p.Arg295Thr	missense_variant	7/17	ENST00000294053.9
CLPB	NM_001258392.3	c.794G>C	p.Arg265Thr	missense_variant	6/16	ENST00000538039.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9	c.884G>C	p.Arg295Thr	missense_variant	7/17	1	NM_030813.6	P4
CLPB	ENST00000538039.6	c.794G>C	p.Arg265Thr	missense_variant	6/16	2	NM_001258392.3	A1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2798 AN: 152118 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00459 AC: 1154 AN: 251210 Hom.: 41 AF XY: 0.00338 AC XY: 459 AN XY: 135766

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00191 AC: 2795 AN: 1461574 Hom.: 95 Cov.: 30 AF XY: 0.00168 AC XY: 1221 AN XY: 727106

Gnomad4 AFR exome AF: 0.0711

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.0184 AC: 2796 AN: 152236 Hom.: 91 Cov.: 32 AF XY: 0.0174 AC XY: 1295 AN XY: 74446

Gnomad4 AFR AF: 0.0642

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00273 Hom.: 11

Bravo AF: 0.0212

ESP6500AA AF: 0.0611 AC: 269

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00562 AC: 683

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2016

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. -

CLPB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as 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	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.031	T;.;.;T;.;.;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0022	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0050	N;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.68	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N;N;N;N;N;.;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.18	T;T;T;T;T;.;.;T;D
Sift4G	Benign	0.38	T;T;T;T;T;.;.;.;D
Polyphen		0.0030	B;.;B;.;.;.;.;.;.
Vest4		0.23
MVP		0.68
MPC		0.57
ClinPred		0.010	T
GERP RS		5.4
Varity_R		0.059
gMVP		0.38

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

Other links and lift over

dbSNP: rs7938203; hg19: chr11-72040830;