rs8100489

Positions:

• chr19-6364442-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000245816.11(CLPP):​c.368-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,601,014 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (84 hom., cov: 30)
  • Exomes 𝑓: 0.0018 (95 hom.)
• Consequence: CLPP ENST00000245816.11 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001484
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.738

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-6364442-C-T is Benign according to our data. Variant chr19-6364442-C-T is described in ClinVar as [Benign]. Clinvar id is 226518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLPP	NM_006012.4	c.368-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000245816.11	NP_006003.1
CLPP	XM_047439486.1	c.464-10C>T		splice_polypyrimidine_tract_variant, intron_variant			XP_047295442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLPP	ENST00000245816.11	c.368-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006012.4	ENSP00000245816	P1

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2807 AN: 152038 Hom.: 83 Cov.: 30

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00418 AC: 948 AN: 226564 Hom.: 32 AF XY: 0.00289 AC XY: 358 AN XY: 123922

Gnomad AFR exome AF: 0.0619

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000600

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.00180 AC: 2613 AN: 1448858 Hom.: 95 Cov.: 31 AF XY: 0.00155 AC XY: 1116 AN XY: 720084

Gnomad4 AFR exome AF: 0.0656

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000560

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.0185 AC: 2820 AN: 152156 Hom.: 84 Cov.: 30 AF XY: 0.0176 AC XY: 1312 AN XY: 74392

Gnomad4 AFR AF: 0.0656

Gnomad4 AMR AF: 0.00465

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0114 Hom.: 15

Bravo AF: 0.0210

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	368-10C>T in intron 3 of CLPP: This variant is not expected to have clinical sig nificance because it has been identified in 6.6% (290/4398) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs8100489). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.3
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs8100489; hg19: chr19-6364453;