11-72295612-A-C

Variant names:

• chr11-72295612-A-C
• rs886041118
• NM_030813.6:c.1456T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001258392.3(CLPB):​c.1366T>G​(p.Cys456Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. C456R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLPB NM_001258392.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29
• Publications: 0 publications found

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]

CLPB Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria, type VIIB

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• neutropenia, severe congenital, 9, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255843 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258392.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPB	NM_030813.6	MANE Plus Clinical	c.1456T>G	p.Cys486Gly	missense	Exon 13 of 17	NP_110440.1	A0A140VK11
	CLPB	NM_001258392.3	MANE Select	c.1366T>G	p.Cys456Gly	missense	Exon 12 of 16	NP_001245321.1	Q9H078-2
	CLPB	NM_001258394.3		c.1321T>G	p.Cys441Gly	missense	Exon 14 of 18	NP_001245323.1	Q9H078-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPB	ENST00000294053.9	TSL:1 MANE Plus Clinical	c.1456T>G	p.Cys486Gly	missense	Exon 13 of 17	ENSP00000294053.3	Q9H078-1
	CLPB	ENST00000538039.6	TSL:2 MANE Select	c.1366T>G	p.Cys456Gly	missense	Exon 12 of 16	ENSP00000441518.1	Q9H078-2
	CLPB	ENST00000538021.5	TSL:1	n.*155T>G		non_coding_transcript_exon	Exon 5 of 9	ENSP00000445180.2	F6SS08

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.85		Gain of disorder (P = 0.013)
MVP		0.64
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.93
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs886041118; hg19: chr11-72006656;