rs1555719766

Positions:

• chr19-6366326-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

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).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CLPP NM_006012.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.28

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain ATP-dependent Clp protease proteolytic subunit, mitochondrial (size 220) in uniprot entity CLPP_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) 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 id is 545503.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-6366326-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLPP	NM_006012.4	c.624C>G	p.Ile208Met	missense_variant	5/6	ENST00000245816.11	NP_006003.1
CLPP	XM_047439486.1	c.720C>G	p.Ile240Met	missense_variant	4/5		XP_047295442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLPP	ENST00000245816.11	c.624C>G	p.Ile208Met	missense_variant	5/6	1	NM_006012.4	ENSP00000245816.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Perrault syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.22
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.031	D;D
Polyphen		0.88	P;.
Vest4		0.77
MutPred		0.76		Gain of disorder (P = 0.0452);.;
MVP		0.55
MPC		1.7
ClinPred		0.88	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.89

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: rs1555719766; hg19: chr19-6366337;