Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_006012.4(CLPP):c.624C>G(p.Ile208Met) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I208V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

CLPP
NM_006012.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.28

Publications

2 publications found

Variant links:

Genes affected

CLPP (HGNC:2084): (caseinolytic mitochondrial matrix peptidase proteolytic subunit) The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]

CLPP Gene-Disease associations (from GenCC):

Perrault syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
Perrault syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLPP links:

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ACMG classification

Classification was made for transcript

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

PM1

In a chain ATP-dependent Clp protease proteolytic subunit, mitochondrial (size 220) in uniprot entity CLPP_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_006012.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.817

PP5

Variant 19-6366326-C-G is Pathogenic according to our data. Variant chr19-6366326-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 545503.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPP	NM_006012.4	MANE Select	c.624C>G	p.Ile208Met	missense	Exon 5 of 6	NP_006003.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLPP	ENST00000245816.11	TSL:1 MANE Select	c.624C>G	p.Ile208Met	missense	Exon 5 of 6	ENSP00000245816.3
CLPP	ENST00000715787.1		c.624C>G	p.Ile208Met	missense	Exon 5 of 6	ENSP00000520519.1
CLPP	ENST00000596149.5	TSL:2	c.363C>G	p.Ile121Met	missense	Exon 4 of 5	ENSP00000472227.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Perrault syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.011

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.2

PhyloP100

2.3

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.4

REVEL

Benign

0.22

Sift

Uncertain

0.012

Sift4G

Uncertain

0.031

Polyphen

0.88

Vest4

0.77

MutPred

0.76

Gain of disorder (P = 0.0452)

MVP

0.55

MPC

1.7

ClinPred

0.88

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.89

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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rs1555719766

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over