Variant 1-223712723-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001748.5(CAPN2):c.83T>C(p.Leu28Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,586,274 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CAPN2
NM_001748.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAPN2	NM_001748.5 linkuse as main transcript	c.83T>C	p.Leu28Pro	missense_variant	1/21	ENST00000295006.6
CAPN2	XM_047431344.1 linkuse as main transcript	c.83T>C	p.Leu28Pro	missense_variant	1/12
CAPN2	NM_001146068.2 linkuse as main transcript	c.4-5039T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN2	ENST00000295006.6 linkuse as main transcript	c.83T>C	p.Leu28Pro	missense_variant	1/21	1	NM_001748.5	P1	P17655-1
CAPN2	ENST00000433674.6 linkuse as main transcript	c.4-5039T>C		intron_variant		2			P17655-2
CAPN2	ENST00000434648.5 linkuse as main transcript	c.4-5039T>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151536

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1434738

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712682

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151536

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74030

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000829

AC:

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

Mar 06, 2023

The c.83T>C (p.L28P) alteration is located in exon 1 (coding exon 1) of the CAPN2 gene. This alteration results from a T to C substitution at nucleotide position 83, causing the leucine (L) at amino acid position 28 to be replaced by a proline (P). 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

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.15

Cadd

Uncertain

Dann

Benign

0.95

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.011

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.75

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.28

Sift

Benign

0.13

Sift4G

Benign

0.27

Polyphen

0.99

Vest4

0.64

MutPred

0.57

Loss of stability (P = 0.0094);

MVP

0.34

MPC

0.71

ClinPred

0.95

GERP RS

3.1

Varity_R

0.93

gMVP

0.85

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