11-72293441-C-T

Position:

• chr11-72293441-C-T

Variant summary

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

The NM_030813.6(CLPB):​c.2050G>A​(p.Asp684Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000342 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D684H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: CLPB NM_030813.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

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=0.19535315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_030813.6	c.2050G>A	p.Asp684Asn	missense_variant	17/17	ENST00000294053.9
CLPB	NM_001258392.3	c.1960G>A	p.Asp654Asn	missense_variant	16/16	ENST00000538039.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9	c.2050G>A	p.Asp684Asn	missense_variant	17/17	1	NM_030813.6	P4
CLPB	ENST00000538039.6	c.1960G>A	p.Asp654Asn	missense_variant	16/16	2	NM_001258392.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251396 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727236

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: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Invitae

Jan 07, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 684 of the CLPB protein (p.Asp684Asn). This variant is present in population databases (rs781355066, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CLPB-related conditions. ClinVar contains an entry for this variant (Variation ID: 2159908). 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	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T;.;.;T;.;.
Eigen	Benign	0.092
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.73	N;N;N;N;N;.
REVEL	Benign	0.099
Sift	Benign	0.077	T;T;T;T;T;.
Sift4G	Benign	0.15	T;T;T;T;T;.
Polyphen		0.97	D;.;B;.;.;.
Vest4		0.15
MutPred		0.33		Loss of loop (P = 0.0073);.;.;.;.;.;
MVP		0.63
MPC		0.42
ClinPred		0.11	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.52

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: rs781355066; hg19: chr11-72004485; COSMIC: COSV53628099; COSMIC: COSV53628099;