rs112620134

Variant names:

• chr19-6368677-G-A
• rs112620134
• NM_006012.4:c.801G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006012.4(CLPP):​c.801G>A​(p.Ala267Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,566,892 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (13 hom., cov: 32)
  • Exomes 𝑓: 0.011 (87 hom.)
• Consequence: CLPP NM_006012.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.98
• Publications: 6 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), PanelApp Australia, G2P
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-6368677-G-A is Benign according to our data. Variant chr19-6368677-G-A is described in ClinVar as Benign. ClinVar VariationId is 226523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00961 (1463/152234) while in subpopulation NFE AF = 0.0132 (895/68006). AF 95% confidence interval is 0.0124. There are 13 homozygotes in GnomAd4. There are 725 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.801G>A	p.Ala267Ala	synonymous	Exon 6 of 6	NP_006003.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPP	ENST00000245816.11	TSL:1 MANE Select	c.801G>A	p.Ala267Ala	synonymous	Exon 6 of 6	ENSP00000245816.3
	CLPP	ENST00000715787.1		c.801G>A	p.Ala267Ala	synonymous	Exon 6 of 6	ENSP00000520519.1
	CLPP	ENST00000926271.1		c.729G>A	p.Ala243Ala	synonymous	Exon 5 of 5	ENSP00000596330.1

Frequencies

GnomAD3 genomes AF: 0.00962 AC: 1464 AN: 152116 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00813 AC: 1395 AN: 171522 AF XY: 0.00797

Gnomad AFR exome AF: 0.00604

Gnomad AMR exome AF: 0.00473

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.00935

GnomAD4 exome AF: 0.0112 AC: 15796 AN: 1414658 Hom.: 87 Cov.: 31 AF XY: 0.0110 AC XY: 7683 AN XY: 699678

African (AFR) AF: 0.00724 AC: 232 AN: 32054

American (AMR) AF: 0.00511 AC: 191 AN: 37412

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 344 AN: 25366

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36666

South Asian (SAS) AF: 0.00239 AC: 194 AN: 81098

European-Finnish (FIN) AF: 0.00588 AC: 295 AN: 50160

Middle Eastern (MID) AF: 0.00587 AC: 32 AN: 5454

European-Non Finnish (NFE) AF: 0.0127 AC: 13850 AN: 1087814

Other (OTH) AF: 0.0112 AC: 657 AN: 58634

GnomAD4 genome AF: 0.00961 AC: 1463 AN: 152234 Hom.: 13 Cov.: 32 AF XY: 0.00974 AC XY: 725 AN XY: 74430

African (AFR) AF: 0.00700 AC: 291 AN: 41544

American (AMR) AF: 0.0106 AC: 162 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 895 AN: 68006

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.0120 Hom.: 11

Bravo AF: 0.00961

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.11
DANN	Benign	0.43
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs112620134; hg19: chr19-6368688; COSMIC: COSV55534987; COSMIC: COSV55534987;