chr19-6361660-C-T

Variant names:

• chr19-6361660-C-T
• NM_006012.4:c.86C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006012.4(CLPP):​c.86C>T​(p.Pro29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000078 in 1,281,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P29S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: CLPP NM_006012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.369
• Publications: 0 publications found

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, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000269802 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062315255).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPP	NM_006012.4	MANE Select	c.86C>T	p.Pro29Leu	missense	Exon 1 of 6	NP_006003.1	Q16740

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPP	ENST00000245816.11	TSL:1 MANE Select	c.86C>T	p.Pro29Leu	missense	Exon 1 of 6	ENSP00000245816.3	Q16740
	CLPP	ENST00000715787.1		c.86C>T	p.Pro29Leu	missense	Exon 1 of 6	ENSP00000520519.1	Q16740
	CLPP	ENST00000926271.1		c.86C>T	p.Pro29Leu	missense	Exon 1 of 5	ENSP00000596330.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.80e-7 AC: 1 AN: 1281794 Hom.: 0 Cov.: 32 AF XY: 0.00000160 AC XY: 1 AN XY: 623130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25710

American (AMR) AF: 0.00 AC: 0 AN: 20802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19090

East Asian (EAS) AF: 0.00 AC: 0 AN: 30828

South Asian (SAS) AF: 0.00 AC: 0 AN: 63486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5138

European-Non Finnish (NFE) AF: 9.74e-7 AC: 1 AN: 1026912

Other (OTH) AF: 0.00 AC: 0 AN: 53084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.37
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.037
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.0	B
Vest4		0.11
MutPred		0.26		Gain of helix (P = 0.0093)
MVP		0.068
MPC		0.77
ClinPred		0.10	T
GERP RS		2.5
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.23
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

hg19: chr19-6361671;