11-65182889-C-T

Variant names:

• chr11-65182889-C-T
• NM_005186.4:c.188C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_005186.4(CAPN1):​c.188C>T​(p.Pro63Leu) variant causes a missense change. 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAPN1 NM_005186.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.00

Genes affected

CAPN1 (HGNC:1476): (calpain 1) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme, calpain 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Calpain catalytic (size 299) in uniprot entity CAN1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_005186.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN1	NM_005186.4	c.188C>T	p.Pro63Leu	missense_variant	Exon 2 of 22	ENST00000279247.11	NP_005177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN1	ENST00000279247.11	c.188C>T	p.Pro63Leu	missense_variant	Exon 2 of 22	1	NM_005186.4	ENSP00000279247.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453696 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722470

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: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.188C>T (p.P63L) alteration is located in exon 2 (coding exon 1) of the CAPN1 gene. This alteration results from a C to T substitution at nucleotide position 188, causing the proline (P) at amino acid position 63 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

May 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 63 of the CAPN1 protein (p.Pro63Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CAPN1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;T;T;T;T;T;.;T;.;T;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;.;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.8	.;.;M;.;.;M;M;M;.;.;.;.;.;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.97	.;.;D;.;.;D;D;D;.;.;.;.;.;D
Vest4		0.32, 0.32, 0.32, 0.27
MutPred		0.81		Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);Loss of catalytic residue at P62 (P = 0.0116);
MVP		0.99
MPC		0.79
ClinPred		0.94	D
GERP RS		4.2
Varity_R		0.22
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr11-64950360;