rs7260547

Variant names:

• chr19-6364489-G-A
• rs7260547
• NM_006012.4:c.405G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-6364489-G-A
• chr19-6364489-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006012.4(CLPP):​c.405G>A​(p.Thr135Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,611,230 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (160 hom., cov: 30)
  • Exomes 𝑓: 0.0026 (154 hom.)
• Consequence: CLPP NM_006012.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.17
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 19-6364489-G-A is Benign according to our data. Variant chr19-6364489-G-A is described in ClinVar as Benign. ClinVar VariationId is 226520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

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.405G>A	p.Thr135Thr	synonymous	Exon 4 of 6	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.405G>A	p.Thr135Thr	synonymous	Exon 4 of 6	ENSP00000245816.3	Q16740
	CLPP	ENST00000597326.6	TSL:5	c.214G>A	p.Asp72Asn	missense	Exon 4 of 6	ENSP00000470098.2	M0QYV5
	CLPP	ENST00000715787.1		c.405G>A	p.Thr135Thr	synonymous	Exon 4 of 6	ENSP00000520519.1	Q16740

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4027 AN: 151934 Hom.: 156 Cov.: 30

Gnomad AFR AF: 0.0920

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.00707 AC: 1728 AN: 244518 AF XY: 0.00508

Gnomad AFR exome AF: 0.0964

Gnomad AMR exome AF: 0.00505

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00263 AC: 3840 AN: 1459178 Hom.: 154 Cov.: 31 AF XY: 0.00216 AC XY: 1569 AN XY: 725858

African (AFR) AF: 0.0912 AC: 3050 AN: 33442

American (AMR) AF: 0.00617 AC: 275 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.000267 AC: 23 AN: 85982

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52498

Middle Eastern (MID) AF: 0.00537 AC: 28 AN: 5218

European-Non Finnish (NFE) AF: 0.0000702 AC: 78 AN: 1111554

Other (OTH) AF: 0.00639 AC: 385 AN: 60236

GnomAD4 genome AF: 0.0266 AC: 4051 AN: 152052 Hom.: 160 Cov.: 30 AF XY: 0.0258 AC XY: 1915 AN XY: 74344

African (AFR) AF: 0.0923 AC: 3825 AN: 41446

American (AMR) AF: 0.0101 AC: 154 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67996

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.00754 Hom.: 99

Bravo AF: 0.0306

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	2.2
DANN	Benign	0.81
PhyloP100		-1.2
PromoterAI		0.028	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs7260547; hg19: chr19-6364500;