19-6361616-A-G

Variant names:

• chr19-6361616-A-G
• rs935069392
• NM_006012.4:c.42A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_006012.4(CLPP):​c.42A>G​(p.Ser14Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000789 in 1,266,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S14S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: CLPP NM_006012.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000269802 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPP	NM_006012.4	c.42A>G	p.Ser14Ser	synonymous_variant	Exon 1 of 6	ENST00000245816.11	NP_006003.1
CLPP	XM_047439486.1	c.42A>G	p.Ser14Ser	synonymous_variant	Exon 1 of 5		XP_047295442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPP	ENST00000245816.11	c.42A>G	p.Ser14Ser	synonymous_variant	Exon 1 of 6	1	NM_006012.4	ENSP00000245816.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.89e-7 AC: 1 AN: 1266650 Hom.: 0 Cov.: 31 AF XY: 0.00000163 AC XY: 1 AN XY: 614188

⚠️ 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: 24574

American (AMR) AF: 0.00 AC: 0 AN: 17584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17654

East Asian (EAS) AF: 0.00 AC: 0 AN: 30022

South Asian (SAS) AF: 0.00 AC: 0 AN: 58248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5036

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1018412

Other (OTH) AF: 0.0000192 AC: 1 AN: 52082

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.6
DANN	Benign	0.49
PhyloP100		-1.1
PromoterAI		-0.082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs935069392; hg19: chr19-6361627;