Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The ENST00000648180.1(CAPN5):c.728G>T(p.Arg243Leu) variant causes a missense change involving the alteration of a 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CAPN5
ENST00000648180.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 8.01

Publications

26 publications found

Variant links:

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]

CAPN5 Gene-Disease associations (from GenCC):

CAPN5-related vitreoretinopathy
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
autosomal dominant neovascular inflammatory vitreoretinopathy
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

CAPN5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000648180.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

PP5

Variant 11-77115423-G-T is Pathogenic according to our data. Variant chr11-77115423-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000648180.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAPN5	NM_004055.5	MANE Select	c.728G>T	p.Arg243Leu	missense	Exon 6 of 13	NP_004046.2
CAPN5	NM_001425321.1		c.848G>T	p.Arg283Leu	missense	Exon 7 of 14	NP_001412250.1
CAPN5	NM_001425322.1		c.728G>T	p.Arg243Leu	missense	Exon 7 of 14	NP_001412251.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAPN5	ENST00000648180.1	MANE Select	c.728G>T	p.Arg243Leu	missense	Exon 6 of 13	ENSP00000498132.1
CAPN5	ENST00000529629.5	TSL:1	c.728G>T	p.Arg243Leu	missense	Exon 7 of 14	ENSP00000432332.1
CAPN5	ENST00000456580.6	TSL:2	c.848G>T	p.Arg283Leu	missense	Exon 7 of 14	ENSP00000409996.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000181

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Proliferative vitreoretinopathy (1)

Autosomal dominant neovascular inflammatory vitreoretinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

8.0

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.43

Sift

Benign

0.040

Sift4G

Benign

0.31

Polyphen

1.0

Vest4

0.88

MutPred

0.60

Loss of methylation at R283 (P = 0.0438)

MVP

0.28

MPC

0.68

ClinPred

0.98

GERP RS

5.1

Varity_R

0.64

gMVP

0.83

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over