chr19-6364444-G-A

Variant names:

• chr19-6364444-G-A
• rs143053584
• NM_006012.4:c.368-8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006012.4(CLPP):​c.368-8G>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 0.00797 in 1,601,524 control chromosomes in the GnomAD database, including 87 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 30)
  • Exomes 𝑓: 0.0082 (80 hom.)
• Consequence: CLPP NM_006012.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007057
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.17
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-6364444-G-A is Benign according to our data. Variant chr19-6364444-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226519.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 = 0.0058 (882/152084) while in subpopulation NFE AF = 0.00875 (595/67994). AF 95% confidence interval is 0.00817. There are 7 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.368-8G>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.368-8G>A		splice_region intron	N/A	ENSP00000245816.3	Q16740
	CLPP	ENST00000715787.1		c.368-8G>A		splice_region intron	N/A	ENSP00000520519.1	Q16740
	CLPP	ENST00000926271.1		c.296-8G>A		splice_region intron	N/A	ENSP00000596330.1

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 882 AN: 151966 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00957

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00875

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00657 AC: 1495 AN: 227694 AF XY: 0.00661

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.0000581

Gnomad FIN exome AF: 0.00950

Gnomad NFE exome AF: 0.00913

Gnomad OTH exome AF: 0.00816

GnomAD4 exome AF: 0.00820 AC: 11883 AN: 1449440 Hom.: 80 Cov.: 31 AF XY: 0.00822 AC XY: 5923 AN XY: 720450

African (AFR) AF: 0.000964 AC: 32 AN: 33182

American (AMR) AF: 0.00361 AC: 157 AN: 43434

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 183 AN: 25842

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39030

South Asian (SAS) AF: 0.00601 AC: 509 AN: 84658

European-Finnish (FIN) AF: 0.00950 AC: 490 AN: 51574

Middle Eastern (MID) AF: 0.00403 AC: 17 AN: 4220

European-Non Finnish (NFE) AF: 0.00900 AC: 9968 AN: 1107788

Other (OTH) AF: 0.00881 AC: 526 AN: 59712

GnomAD4 genome AF: 0.00580 AC: 882 AN: 152084 Hom.: 7 Cov.: 30 AF XY: 0.00541 AC XY: 402 AN XY: 74354

African (AFR) AF: 0.00111 AC: 46 AN: 41462

American (AMR) AF: 0.00432 AC: 66 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4832

European-Finnish (FIN) AF: 0.00957 AC: 101 AN: 10556

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00875 AC: 595 AN: 67994

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00817 Hom.: 6

Bravo AF: 0.00504

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	CLPP-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.20
DANN	Benign	0.56
PhyloP100		-1.2
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.0
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: rs143053584; hg19: chr19-6364455;