rs876657442

Variant names:

• chr19-6368560-C-T
• rs876657442
• NM_006012.4:c.684C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_006012.4(CLPP):​c.684C>T​(p.Arg228Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLPP NM_006012.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.527
• 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

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=0.12521762).
• BP6: Variant 19-6368560-C-T is Benign according to our data. Variant chr19-6368560-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227256.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPP	NM_006012.4	MANE Select	c.684C>T	p.Arg228Arg	synonymous	Exon 6 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.684C>T	p.Arg228Arg	synonymous	Exon 6 of 6	ENSP00000245816.3	Q16740
	CLPP	ENST00000646643.1		c.95C>T	p.Ala32Val	missense	Exon 2 of 2	ENSP00000494298.1	A0A2R8YEF5
	CLPP	ENST00000715787.1		c.684C>T	p.Arg228Arg	synonymous	Exon 6 of 6	ENSP00000520519.1	Q16740

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000612 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.6
DANN	Benign	0.81
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.13	T
PhyloP100		-0.53
GERP RS		-3.8
Mutation Taster		=99/1	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

dbSNP: rs876657442; hg19: chr19-6368571;