11-77084962-C-T

Position:

• chr11-77084962-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004055.5(CAPN5):​c.76C>T​(p.Leu26Phe) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAPN5 NM_004055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN5	NM_004055.5	c.76C>T	p.Leu26Phe	missense_variant	2/13	ENST00000648180.1	NP_004046.2
CAPN5	XM_011545225.1	c.196C>T	p.Leu66Phe	missense_variant	3/14		XP_011543527.1
CAPN5	XM_017018223.3	c.184C>T	p.Leu62Phe	missense_variant	2/13		XP_016873712.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN5	ENST00000648180.1	c.76C>T	p.Leu26Phe	missense_variant	2/13		NM_004055.5	ENSP00000498132	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) performed at Invitae indicates that this missense variant is expected to disrupt CAPN5 protein function. This variant has not been reported in the literature in individuals affected with CAPN5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 26 of the CAPN5 protein (p.Leu26Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;T;D;D;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D;D;.;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.049	D;D;.;D;T
Sift4G	Benign	0.083	T;D;.;T;T
Polyphen		1.0	D;.;D;D;D
Vest4		0.78
MutPred		0.92		Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);Loss of MoRF binding (P = 0.1374);
MVP		0.94
MPC		0.68
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-76796008;