11-65210073-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005186.4(CAPN1):​c.1919T>G​(p.Met640Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

CAPN1
NM_005186.4 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88
Variant links:
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]

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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, 0.949

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CAPN1NM_005186.4 linkc.1919T>G p.Met640Arg missense_variant 19/22 ENST00000279247.11 NP_005177.2 P07384

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CAPN1ENST00000279247.11 linkc.1919T>G p.Met640Arg missense_variant 19/221 NM_005186.4 ENSP00000279247.7 P07384

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
31

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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 05, 2016The p.Met640Arg variant in CAPN1 has not been previously reported in the literat ure and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, the clinical significance of the p.Met640Arg variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;D;D;D;D
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;.;.;.;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D
MetaSVM
Uncertain
-0.036
T
MutationAssessor
Pathogenic
3.4
M;M;M;M;M
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-5.4
D;D;D;D;D
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;D;D;D;D
Vest4
0.95
MutPred
0.81
Gain of methylation at M640 (P = 0.0311);Gain of methylation at M640 (P = 0.0311);Gain of methylation at M640 (P = 0.0311);Gain of methylation at M640 (P = 0.0311);Gain of methylation at M640 (P = 0.0311);
MVP
0.89
MPC
1.3
ClinPred
0.99
D
GERP RS
3.5
Varity_R
0.95
gMVP
0.99

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.

Other links and lift over

dbSNP: rs752166957; hg19: chr11-64977544; API