11-65182765-C-T

Variant summary

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

The NM_005186.4(CAPN1):c.64C>T(p.Arg22Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,428,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CAPN1 NM_005186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.456

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	UniProt
CAPN1	NM_005186.4	c.64C>T	p.Arg22Trp	missense_variant	2/22	ENST00000279247.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN1	ENST00000279247.11	c.64C>T	p.Arg22Trp	missense_variant	2/22	1	NM_005186.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1428586 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 707770

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.0000512

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Invitae

Sep 07, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1352010). This variant has not been reported in the literature in individuals affected with CAPN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 22 of the CAPN1 protein (p.Arg22Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.094	T;T;D;T;T;D;D;D;.;T;.;T;.;D
Eigen	Benign	0.11
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.93	D;D;.;.;D;.;.;.;D;D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.12
Sift	Benign	0.099	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.097	T;T;T;T;T;T;T;T;D;T;T;T;T;T
Polyphen		0.41	.;.;B;.;.;B;B;B;.;.;.;.;.;B
Vest4		0.19, 0.19, 0.19, 0.19, 0.16
MutPred		0.46		Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);Loss of disorder (P = 0.0119);
MVP		0.98
MPC		0.35
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
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

LitVar

Other links and lift over

dbSNP: rs1565385504; hg19: chr11-64950236;