dbSNP rs398123035: CLPP:c.270+4A>G (chr19-6361944-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_006012.4(CLPP):c.270+4A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLPP
NM_006012.4 splice_region, intron

Scores

Splicing: ADA: 0.9990

Clinical Significance

Pathogenic no assertion criteria provided P:2O:1

Conservation

PhyloP100: 4.32

Publications

8 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:

ENSG00000269802 (HGNC:):

ENSG00000269802 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 19-6361944-A-G is Pathogenic according to our data. Variant chr19-6361944-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 55870.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPP	NM_006012.4 link	c.270+4A>G		splice_region_variant, intron_variant	Intron 2 of 5	ENST00000245816.11	NP_006003.1
CLPP	XM_047439486.1 link	c.366+4A>G		splice_region_variant, intron_variant	Intron 1 of 4		XP_047295442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPP	ENST00000245816.11 link	c.270+4A>G		splice_region_variant, intron_variant	Intron 2 of 5	1	NM_006012.4	ENSP00000245816.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1444632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719094

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110850

Other (OTH)

AF:

0.00

AC:

AN:

60042

GnomAD4 genome

Cov.:

Alfa

AF:

0.000600

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Perrault syndrome 3

Pathogenic:1

Apr 04, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Autosomal recessive hearing impairment with normal menstrual cycles

Pathogenic:1

Jun 17, 2013

Department of Molecular and Human Genetics, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Perrault syndrome

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

4.3

PromoterAI

-0.20

Neutral

(source)

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.49

Position offset: -20

DS_DL_spliceai

0.25

Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over