11-72293375-T-G

Variant names:

• chr11-72293375-T-G
• rs112524097
• NM_030813.6:c.2116A>C

Variant summary

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

The NM_001258392.3(CLPB):​c.2026A>C​(p.Thr676Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T676A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLPB NM_001258392.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

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 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=0.24530712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPB	NM_030813.6	c.2116A>C	p.Thr706Pro	missense_variant	Exon 17 of 17	ENST00000294053.9	NP_110440.1
CLPB	NM_001258392.3	c.2026A>C	p.Thr676Pro	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.2116A>C	p.Thr706Pro	missense_variant	Exon 17 of 17	1	NM_030813.6	ENSP00000294053.3
CLPB	ENST00000538039.6	c.2026A>C	p.Thr676Pro	missense_variant	Exon 16 of 16	2	NM_001258392.3	ENSP00000441518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.;.;T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.62	T;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.0	L;.;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.080	N;N;N;N;N;.
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D;D;D;D;D;.
Sift4G	Uncertain	0.014	D;D;D;D;D;.
Polyphen		0.41	B;.;P;.;.;.
Vest4		0.21
MutPred		0.15		Gain of ubiquitination at K702 (P = 0.0469);.;.;.;.;.;
MVP		0.72
MPC		0.74
ClinPred		0.63	D
GERP RS		6.1
Varity_R		0.10
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112524097; hg19: chr11-72004419;