11-65182950-C-G

Position:

• chr11-65182950-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000279247.11(CAPN1):​c.249C>G​(p.Ile83Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAPN1 ENST00000279247.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.132

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN1	NM_005186.4	c.249C>G	p.Ile83Met	missense_variant	2/22	ENST00000279247.11	NP_005177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN1	ENST00000279247.11	c.249C>G	p.Ile83Met	missense_variant	2/22	1	NM_005186.4	ENSP00000279247	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Jul 17, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 83 of the CAPN1 protein (p.Ile83Met). 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. ClinVar contains an entry for this variant (Variation ID: 2000531). 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 not expected to disrupt CAPN1 protein function. 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	Benign	0.22
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T;T;T;T;T;T;T;.;T;.;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.91	D;D;.;.;D;.;.;.;D;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.2	.;.;M;.;.;M;M;M;.;.;.;.;M
MutationTaster	Benign	0.83	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	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
Polyphen		0.86	.;.;P;.;.;P;P;P;.;.;.;.;P
Vest4		0.23, 0.23, 0.23, 0.23, 0.18
MutPred		0.74		Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);Loss of methylation at K84 (P = 0.0371);
MVP		0.87
MPC		0.46
ClinPred		0.96	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.61

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: chr11-64950421;