rs886041303

Positions:

• chr11-77115560-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_004055.5(CAPN5):​c.865C>T​(p.Arg289Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAPN5 NM_004055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.49

Genes affected

CAPN5 (HGNC:1482): (calpain 5) Calpains are calcium-dependent cysteine proteases involved in signal transduction in a variety of cellular processes. A functional calpain protein consists of an invariant small subunit and 1 of a family of large subunits. CAPN5 is one of the large subunits. Unlike some of the calpains, CAPN5 and CAPN6 lack a calmodulin-like domain IV. Because of the significant similarity to Caenorhabditis elegans sex determination gene tra-3, CAPN5 is also called as HTRA3. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 11-77115560-C-T is Pathogenic according to our data. Variant chr11-77115560-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 279987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN5	NM_004055.5	c.865C>T	p.Arg289Trp	missense_variant	6/13	ENST00000648180.1	NP_004046.2
CAPN5	XM_011545225.1	c.985C>T	p.Arg329Trp	missense_variant	7/14		XP_011543527.1
CAPN5	XM_017018223.3	c.973C>T	p.Arg325Trp	missense_variant	6/13		XP_016873712.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN5	ENST00000648180.1	c.865C>T	p.Arg289Trp	missense_variant	6/13		NM_004055.5	ENSP00000498132.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Proliferative vitreoretinopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	May 25, 2020	- -
Pathogenic, no assertion criteria provided	research	Omics Laboratory, Stanford University	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2021	Published functional studies demonstrate altered enzymatic activity (Velez et al., 2018) and the mutant mouse model exhibits a phenotype similar to that seen in humans (Wang et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32707200, 30986125, 31403230, 29472286, 29610848, 29245980) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN5 function (PMID: 29472286). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN5 protein function. ClinVar contains an entry for this variant (Variation ID: 279987). This missense change has been observed in individual(s) with autosomal dominant neovascular inflammatory vitreoretinopathy (PMID: 29472286, 30986125). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 289 of the CAPN5 protein (p.Arg289Trp). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.865C>T (p.R289W) alteration is located in exon 6 (coding exon 5) of the CAPN5 gene. This alteration results from a C to T substitution at nucleotide position 865, causing the arginine (R) at amino acid position 289 to be replaced by a tryptophan (W). The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CAPN5 c.865C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported in a large Chinese family with 9 individuals in 4 generations affected with vitreoretinopathy, cataracts and retinitis pigmentosa starting in childhood, and it segregated with all affected individuals in that family (Wang, 2018). In addition, it has been reported de novo in two unrelated patients with vitreoretinopathy, hearing loss, and additional findings (O'Keefe, 2019; Velez, 2018). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R289 amino acid is conserved in available vertebrate species through reptiles. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ A mouse model harboring this alteration was found to have an abnormally proliferative retinal pigment epithelium (RPE) layer (Wang, 2018) and in vitro studies have demostrated a gain-of-function effect with hyperactivation of the calpain protease even in the absence of calcium levels typically required for activation of wild type CAPN5 (Velez, 2018). The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.R289W alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

CAPN5-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2024

The CAPN5 c.865C>T variant is predicted to result in the amino acid substitution p.Arg289Trp. This variant has been reported as de novo in four pediatric patients with vitreoretinopathy phenotypes (Velez et al. 2018. PubMed ID: 29472286; O'Keefe et al. 2019. PubMed ID: 30986125; Xia et al. 2022. PubMed ID: 36369866). This variant was also reported in a patient from a posterior segment uveitis cohort (Li et al. 2020. PubMed ID: 32707200). A functional analysis showed that this variant had a gain of function effect, leading to increased the proteolytic activity of CAPN5 (Velez et al. 2018. PubMed ID: 29472286). This variant has not been reported in a large population database, indicating this variant is rare and has been interpreted as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/279987/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;D;D;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.96	.;.;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.9	M;M;M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.2	D;.;D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D;.;D;D;.
Sift4G	Uncertain	0.0090	D;.;D;D;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.66
MutPred		0.60		.;.;.;Loss of disorder (P = 0.0182);.;
MVP		0.93
MPC		0.65
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.93
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041303; hg19: chr11-76826606;