11-72293394-G-T

Variant names:

• chr11-72293394-G-T
• rs893345264
• NM_030813.6:c.2097C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001258392.3(CLPB):​c.2007C>A​(p.His669Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CLPB NM_001258392.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12275332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPB	NM_030813.6	c.2097C>A	p.His699Gln	missense_variant	Exon 17 of 17	ENST00000294053.9	NP_110440.1
CLPB	NM_001258392.3	c.2007C>A	p.His669Gln	missense_variant	Exon 16 of 16	ENST00000538039.6	NP_001245321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9	c.2097C>A	p.His699Gln	missense_variant	Exon 17 of 17	1	NM_030813.6	ENSP00000294053.3
CLPB	ENST00000538039.6	c.2007C>A	p.His669Gln	missense_variant	Exon 16 of 16	2	NM_001258392.3	ENSP00000441518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB Uncertain:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 699 of the CLPB protein (p.His699Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CLPB-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;.;.;T;.;.
Eigen	Benign	-0.027
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.84	L;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.57	N;N;N;N;N;.
REVEL	Benign	0.023
Sift	Uncertain	0.017	D;D;D;D;D;.
Sift4G	Benign	0.21	T;T;T;T;T;.
Polyphen		0.16	B;.;B;.;.;.
Vest4		0.078
MutPred		0.11		Gain of ubiquitination at K702 (P = 0.0562);.;.;.;.;.;
MVP		0.55
MPC		0.38
ClinPred		0.46	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.58

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: rs893345264; hg19: chr11-72004438;