rs199476325
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2
The NM_033337.3(CAV3):c.100G>A(p.Glu34Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,601,948 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
CAV3
NM_033337.3 missense
NM_033337.3 missense
Scores
4
6
8
Clinical Significance
Conservation
PhyloP100: 6.40
Genes affected
CAV3 (HGNC:1529): (caveolin 3) This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_033337.3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.853
BS2
?
High AC in GnomAdExome4 at 39 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAV3 | NM_033337.3 | c.100G>A | p.Glu34Lys | missense_variant | 1/2 | ENST00000343849.3 | |
CAV3 | NM_001234.5 | c.100G>A | p.Glu34Lys | missense_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAV3 | ENST00000343849.3 | c.100G>A | p.Glu34Lys | missense_variant | 1/2 | 1 | NM_033337.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151984Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251124Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135758
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GnomAD4 exome AF: 0.0000269 AC: 39AN: 1449846Hom.: 0 Cov.: 28 AF XY: 0.0000291 AC XY: 21AN XY: 722100
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152102Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Rippling muscle disease 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Center for Genetic Medicine Research, Children's National Medical Center | Dec 01, 2015 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 09, 2017 | - - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 29, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 34 of the CAV3 protein (p.Glu34Lys). This variant is present in population databases (rs199476325, gnomAD 0.005%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (LGMD) (PMID: 17897828, 27854218). This variant is also known as p.Glu33Lys. ClinVar contains an entry for this variant (Variation ID: 31730). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2020 | The c.100G>A (p.E34K) alteration is located in exon 1 (coding exon 1) of the CAV3 gene. This alteration results from a G to A substitution at nucleotide position 100, causing the glutamic acid (E) at amino acid position 34 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Other:1
not provided, no classification provided | curation | Leiden Muscular Dystrophy (CAV3) | Apr 15, 2012 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
P;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at