rs545353866

chr19-6361567-G-GCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006012.4(CLPP):c.-7_-6insCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,397,388 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: CLPP NM_006012.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.590

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-6361567-G-GCC is Benign according to our data. Variant chr19-6361567-G-GCC is described in ClinVar as [Likely_benign]. Clinvar id is 504858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00144 (220/152354) while in subpopulation NFE AF= 0.00218 (148/68040). AF 95% confidence interval is 0.00189. There are 2 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPP	NM_006012.4	c.-7_-6insCC		5_prime_UTR_variant	1/6	ENST00000245816.11
CLPP	XM_047439486.1	c.-7_-6insCC		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPP	ENST00000245816.11	c.-7_-6insCC		5_prime_UTR_variant	1/6	1	NM_006012.4	P1
	ENST00000595644.1	n.35+547_35+548insGG		intron_variant, non_coding_transcript_variant		4
CLPP	ENST00000596070.1	n.4_5insCC		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152236 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00217

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00140 AC: 65 AN: 46530 Hom.: 0 AF XY: 0.00133 AC XY: 31 AN XY: 23262

Gnomad AFR exome AF: 0.000444

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00523

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00104

Gnomad FIN exome AF: 0.000400

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.000954

GnomAD4 exome AF: 0.00184 AC: 2297 AN: 1245034 Hom.: 3 Cov.: 31 AF XY: 0.00193 AC XY: 1159 AN XY: 600774

Gnomad4 AFR exome AF: 0.0000831

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00576

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000528

Gnomad4 FIN exome AF: 0.000587

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00198

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152354 Hom.: 2 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74490

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000724 Hom.: 0

Bravo AF: 0.00148

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 20, 2016	c.-7_-6insCC in exon 1 of CLPP: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (19/2910) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs545353866). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs545353866; hg19: chr19-6361578;