11-77084923-T-C

Position:

• chr11-77084923-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004055.5(CAPN5):​c.37T>C​(p.Tyr13His) 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: 7.48

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN5	NM_004055.5	c.37T>C	p.Tyr13His	missense_variant	2/13	ENST00000648180.1	NP_004046.2
CAPN5	XM_011545225.1	c.157T>C	p.Tyr53His	missense_variant	3/14		XP_011543527.1
CAPN5	XM_017018223.3	c.145T>C	p.Tyr49His	missense_variant	2/13		XP_016873712.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN5	ENST00000648180.1	c.37T>C	p.Tyr13His	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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.37T>C (p.Y13H) alteration is located in exon 2 (coding exon 1) of the CAPN5 gene. This alteration results from a T to C substitution at nucleotide position 37, causing the tyrosine (Y) at amino acid position 13 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;T;D;D;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D;.;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.4	M;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.5	D;D;.;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;.;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.71
MutPred		0.66		Loss of phosphorylation at Y13 (P = 0.0231);Loss of phosphorylation at Y13 (P = 0.0231);Loss of phosphorylation at Y13 (P = 0.0231);Loss of phosphorylation at Y13 (P = 0.0231);Loss of phosphorylation at Y13 (P = 0.0231);
MVP		0.56
MPC		0.70
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.75
gMVP		0.83

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: chr11-76795969;