rs200101759

Variant names:

• chr19-6364642-G-A
• rs200101759
• NM_006012.4:c.555+3G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006012.4(CLPP):​c.555+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,607,686 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 30)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: CLPP NM_006012.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002720
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.33
• 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), G2P
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 19-6364642-G-A is Benign according to our data. Variant chr19-6364642-G-A is described in ClinVar as Benign. ClinVar VariationId is 226521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00253 (384/152014) while in subpopulation AFR AF = 0.0089 (369/41454). AF 95% confidence interval is 0.00815. There are 3 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.555+3G>A		splice_region intron	N/A	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.555+3G>A		splice_region intron	N/A	ENSP00000245816.3	Q16740
	CLPP	ENST00000715787.1		c.555+3G>A		splice_region intron	N/A	ENSP00000520519.1	Q16740
	CLPP	ENST00000926271.1		c.483+3G>A		splice_region intron	N/A	ENSP00000596330.1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 384 AN: 151904 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000657 AC: 159 AN: 241924 AF XY: 0.000462

Gnomad AFR exome AF: 0.00912

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000511

Gnomad NFE exome AF: 0.00000922

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000259 AC: 377 AN: 1455672 Hom.: 1 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 723762

African (AFR) AF: 0.00912 AC: 305 AN: 33452

American (AMR) AF: 0.000606 AC: 27 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85906

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50162

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110046

Other (OTH) AF: 0.000581 AC: 35 AN: 60238

GnomAD4 genome AF: 0.00253 AC: 384 AN: 152014 Hom.: 3 Cov.: 30 AF XY: 0.00246 AC XY: 183 AN XY: 74314

African (AFR) AF: 0.00890 AC: 369 AN: 41454

American (AMR) AF: 0.000785 AC: 12 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.00269

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.94
PhyloP100		3.3
PromoterAI		0.041	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.012
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: rs200101759; hg19: chr19-6364653;