chr11-72293380-C-A

Position:

• chr11-72293380-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030813.6(CLPB):​c.2111G>T​(p.Cys704Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C704Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLPB NM_030813.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18169785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_030813.6	c.2111G>T	p.Cys704Phe	missense_variant	17/17	ENST00000294053.9
CLPB	NM_001258392.3	c.2021G>T	p.Cys674Phe	missense_variant	16/16	ENST00000538039.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9	c.2111G>T	p.Cys704Phe	missense_variant	17/17	1	NM_030813.6	P4
CLPB	ENST00000538039.6	c.2021G>T	p.Cys674Phe	missense_variant	16/16	2	NM_001258392.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 26, 2020

This sequence change replaces cysteine with phenylalanine at codon 704 of the CLPB protein (p.Cys704Phe). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CLPB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	0.078
BayesDel_addAF	Benign	0.0021	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.040	T;.;.;T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.
MutationTaster	Benign	0.91	D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.88	N;N;N;N;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;.
Polyphen		0.76	P;.;P;.;.;.
Vest4		0.30
MutPred		0.27		Loss of helix (P = 0.0558);.;.;.;.;.;
MVP		0.72
MPC		0.93
ClinPred		0.61	D
GERP RS		5.1
Varity_R		0.67
gMVP		0.46

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: rs372096809; hg19: chr11-72004424;