rs1217350095

Variant names:

• chr19-6361575-A-C
• rs1217350095
• NM_006012.4:c.1A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-6361575-A-C
• chr19-6361575-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_006012.4(CLPP):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,251,624 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CLPP NM_006012.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• 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_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 88 codons. Genomic position: 6361932. Lost 0.314 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>C	p.Met1?	initiator_codon	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.1A>C	p.Met1?	initiator_codon	Exon 1 of 6	ENSP00000245816.3	Q16740
	CLPP	ENST00000715787.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 6	ENSP00000520519.1	Q16740
	CLPP	ENST00000926271.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 5	ENSP00000596330.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 6 AN: 1251624 Hom.: 0 Cov.: 31 AF XY: 0.00000331 AC XY: 2 AN XY: 604504

African (AFR) AF: 0.00 AC: 0 AN: 24186

American (AMR) AF: 0.00 AC: 0 AN: 16058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17298

East Asian (EAS) AF: 0.00 AC: 0 AN: 29492

South Asian (SAS) AF: 0.00 AC: 0 AN: 55932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4896

European-Non Finnish (NFE) AF: 0.00000595 AC: 6 AN: 1007924

Other (OTH) AF: 0.00 AC: 0 AN: 51328

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.81	T
PhyloP100		2.2
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.012	B
Vest4		0.75
MutPred		0.99		Loss of MoRF binding (P = 0.0694)
MVP		0.70
ClinPred		1.0	D
GERP RS		3.5
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.19
Mutation Taster		=35/165	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: rs1217350095; hg19: chr19-6361586;