chr1-223747004-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001748.5(CAPN2):c.568G>A(p.Gly190Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,346 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000051 ( 1 hom. )
Consequence
CAPN2
NM_001748.5 missense
NM_001748.5 missense
Scores
11
5
1
Clinical Significance
Conservation
PhyloP100: 8.07
Genes affected
CAPN2 (HGNC:1479): (calpain 2) 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 2. Multiple heterogeneous transcriptional start sites in the 5' UTR have been reported. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
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, 0.962
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN2 | NM_001748.5 | c.568G>A | p.Gly190Arg | missense_variant | 5/21 | ENST00000295006.6 | |
CAPN2 | NM_001146068.2 | c.334G>A | p.Gly112Arg | missense_variant | 5/21 | ||
CAPN2 | XM_047431344.1 | c.568G>A | p.Gly190Arg | missense_variant | 5/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN2 | ENST00000295006.6 | c.568G>A | p.Gly190Arg | missense_variant | 5/21 | 1 | NM_001748.5 | P1 | |
CAPN2 | ENST00000433674.6 | c.334G>A | p.Gly112Arg | missense_variant | 5/21 | 2 | |||
CAPN2 | ENST00000434648.5 | c.334G>A | p.Gly112Arg | missense_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152086Hom.: 0 Cov.: 30
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.000120 AC: 30AN: 250818Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135534
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GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461142Hom.: 1 Cov.: 29 AF XY: 0.0000688 AC XY: 50AN XY: 726918
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74410
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 20, 2021 | The c.568G>A (p.G190R) alteration is located in exon 5 (coding exon 5) of the CAPN2 gene. This alteration results from a G to A substitution at nucleotide position 568, causing the glycine (G) at amino acid position 190 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;.;D
Vest4
MutPred
0.97
.;.;Gain of solvent accessibility (P = 0.0584);
MVP
MPC
0.68
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at