rs371120549

Variant names:

• chr19-6364654-C-T
• rs371120549
• NM_006012.4:c.555+15C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-6364654-C-T
• chr19-6364654-C-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_006012.4(CLPP):​c.555+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,601,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: CLPP NM_006012.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-6364654-C-T is Benign according to our data. Variant chr19-6364654-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227255.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 = 0.000224 (34/152018) while in subpopulation NFE AF = 0.000397 (27/68016). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

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+15C>T		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+15C>T		intron	N/A	ENSP00000245816.3	Q16740
	CLPP	ENST00000715787.1		c.555+15C>T		intron	N/A	ENSP00000520519.1	Q16740
	CLPP	ENST00000926271.1		c.483+15C>T		intron	N/A	ENSP00000596330.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152018 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000184 AC: 44 AN: 238560 AF XY: 0.000215

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000364

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000456 AC: 661 AN: 1449608 Hom.: 0 Cov.: 31 AF XY: 0.000424 AC XY: 305 AN XY: 720168

African (AFR) AF: 0.0000300 AC: 1 AN: 33356

American (AMR) AF: 0.0000451 AC: 2 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39488

South Asian (SAS) AF: 0.0000818 AC: 7 AN: 85618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48342

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5738

European-Non Finnish (NFE) AF: 0.000560 AC: 620 AN: 1106880

Other (OTH) AF: 0.000483 AC: 29 AN: 60016

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152018 Hom.: 0 Cov.: 30 AF XY: 0.000188 AC XY: 14 AN XY: 74272

African (AFR) AF: 0.0000725 AC: 3 AN: 41380

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68016

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000257

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.35
DANN	Benign	0.43
PhyloP100		-2.0
PromoterAI		-0.0084	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs371120549; hg19: chr19-6364665;