1-223712703-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001748.5(CAPN2):c.63C>A(p.His21Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,579,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CAPN2
NM_001748.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.419

Variant links:

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]

CAPN2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18925586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAPN2	NM_001748.5 linkuse as main transcript	c.63C>A	p.His21Gln	missense_variant	1/21	ENST00000295006.6
CAPN2	XM_047431344.1 linkuse as main transcript	c.63C>A	p.His21Gln	missense_variant	1/12
CAPN2	NM_001146068.2 linkuse as main transcript	c.4-5059C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN2	ENST00000295006.6 linkuse as main transcript	c.63C>A	p.His21Gln	missense_variant	1/21	1	NM_001748.5	P1	P17655-1
CAPN2	ENST00000433674.6 linkuse as main transcript	c.4-5059C>A		intron_variant		2			P17655-2
CAPN2	ENST00000434648.5 linkuse as main transcript	c.4-5059C>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1427362

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

708134

show subpopulations

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:

0.0000247

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.11e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151804

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Feb 07, 2023

The c.63C>A (p.H21Q) alteration is located in exon 1 (coding exon 1) of the CAPN2 gene. This alteration results from a C to A substitution at nucleotide position 63, causing the histidine (H) at amino acid position 21 to be replaced by a glutamine (Q). 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

Benign

0.22

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.30

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.19

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.69

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.37

Sift

Benign

0.076

Sift4G

Benign

0.22

Polyphen

0.86

Vest4

0.17

MutPred

0.36

Gain of ubiquitination at K26 (P = 0.0828);

MVP

0.93

MPC

0.40

ClinPred

0.82

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.19

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over