11-77115423-G-T

Variant names:

• chr11-77115423-G-T
• rs397514601
• NM_004055.5:c.728G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP3 PP5_Very_Strong

The NM_004055.5(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 (★★). ClinVar reports functional evidence for this variant: "SCV001582053: Experimental studies have shown that this missense change affects CAPN5 function (PMID:23055945, 24381307, 25994508)." and additional evidence is available in ClinVar. 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 NM_004055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.01
• Publications: 26 publications found

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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• autosomal dominant neovascular inflammatory vitreoretinopathy

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001582053: Experimental studies have shown that this missense change affects CAPN5 function (PMID: 23055945, 24381307, 25994508).; SCV006334098: Published functional studies found this variant is associated with significantly increased catalytic activity (PMID: 25994508); Transgenic mouse model with this variant exhibits a phenotype similar to that seen in humans (PMID: 24381307, 25994508)
• 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 NM_004055.5
• 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: NM_004055.5. 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
	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	E7EV01
	CAPN5	NM_001425322.1		c.728G>T	p.Arg243Leu	missense	Exon 7 of 14	NP_001412251.1	A0A140VKH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN5	ENST00000648180.1	MANE Select	c.728G>T	p.Arg243Leu	missense	Exon 6 of 13	ENSP00000498132.1	O15484
	CAPN5	ENST00000529629.5	TSL:1	c.728G>T	p.Arg243Leu	missense	Exon 7 of 14	ENSP00000432332.1	O15484
	CAPN5	ENST00000886046.1		c.956G>T	p.Arg319Leu	missense	Exon 7 of 14	ENSP00000556105.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.000181 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	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	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		8.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.43
Sift	Benign	0.040	D
Sift4G	Benign	0.31	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.60		Loss of methylation at R283 (P = 0.0438)
MVP		0.28
MPC		0.68
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.64
gMVP		0.83
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs397514601; hg19: chr11-76826469;