rs1457098622

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000070.3(CAPN3):ā€‹c.2330T>Cā€‹(p.Ile777Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I777V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02
Variant links:
Genes affected
CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-42410949-A-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CAPN3NM_000070.3 linkuse as main transcriptc.2330T>C p.Ile777Thr missense_variant 22/24 ENST00000397163.8 NP_000061.1 P20807-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CAPN3ENST00000397163.8 linkuse as main transcriptc.2330T>C p.Ile777Thr missense_variant 22/241 NM_000070.3 ENSP00000380349.3 P20807-1
CAPN3ENST00000673886.1 linkuse as main transcriptc.335T>C p.Ile112Thr missense_variant 9/11 ENSP00000501155.1 P20807-5
CAPN3ENST00000673928.1 linkuse as main transcriptc.335T>C p.Ile112Thr missense_variant 9/11 ENSP00000501099.1 P20807-5
CAPN3ENST00000674146.1 linkuse as main transcriptc.335T>C p.Ile112Thr missense_variant 10/12 ENSP00000501175.1 P20807-5
CAPN3ENST00000674149.1 linkuse as main transcriptc.335T>C p.Ile112Thr missense_variant 9/11 ENSP00000501112.1 P20807-5
CAPN3ENST00000673743.1 linkuse as main transcriptc.233T>C p.Ile78Thr missense_variant 9/11 ENSP00000500989.1 A0A669KAX6
ENSG00000258461ENST00000495723.1 linkuse as main transcriptn.*2766T>C non_coding_transcript_exon_variant 24/262 ENSP00000492063.1 A0A1W2PQD3
ENSG00000258461ENST00000495723.1 linkuse as main transcriptn.*2766T>C 3_prime_UTR_variant 24/262 ENSP00000492063.1 A0A1W2PQD3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251414
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461872
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727238
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylAug 02, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.;.;D;.;.;.;.;.;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D;.;D;.;D;.
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
.;.;.;M;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.9
.;D;D;D;D;D;D;.;D;D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
.;D;D;D;D;D;D;.;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.99, 1.0, 0.99
.;D;D;D;.;.;.;.;.;.;.
Vest4
0.89
MutPred
0.91
.;.;.;Loss of stability (P = 0.0012);.;.;.;.;.;.;.;
MVP
0.98
MPC
0.59
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.76
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs1457098622; hg19: chr15-42703148; API