rs116840776

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

The NM_033337.3(CAV3):c.216C>G(p.Cys72Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,132 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 8 hom. )

Consequence

CAV3
NM_033337.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:16O:1

Conservation

PhyloP100: 1.13

Variant links:

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]

CAV3 links:

OXTR (HGNC:8529): (oxytocin receptor) The protein encoded by this gene belongs to the G-protein coupled receptor family and acts as a receptor for oxytocin. Its activity is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. The oxytocin-oxytocin receptor system plays an important role in the uterus during parturition. [provided by RefSeq, Jul 2008]

OXTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 46 pathogenic changes around while only 9 benign (84%) in NM_033337.3

BP4

Computational evidence support a benign effect (MetaRNN=0.26156944).

BP6

Variant 3-8745627-C-G is Benign according to our data. Variant chr3-8745627-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8279.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=6, Uncertain_significance=1, not_provided=1}. Variant chr3-8745627-C-G is described in Lovd as [Pathogenic]. Variant chr3-8745627-C-G is described in Lovd as [Benign]. Variant chr3-8745627-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00168 (256/152316) while in subpopulation AMR AF= 0.00392 (60/15300). AF 95% confidence interval is 0.00313. There are 2 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 256 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAV3	NM_033337.3 link	c.216C>G	p.Cys72Trp	missense_variant	Exon 2 of 2	ENST00000343849.3	NP_203123.1	P56539
CAV3	NM_001234.5 link	c.216C>G	p.Cys72Trp	missense_variant	Exon 2 of 3		NP_001225.1	P56539
OXTR	XR_007095681.1 link	n.1885-3025G>C		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAV3	ENST00000343849.3 link	c.216C>G	p.Cys72Trp	missense_variant	Exon 2 of 2	1	NM_033337.3	ENSP00000341940.2	P56539
CAV3	ENST00000397368.2 link	c.216C>G	p.Cys72Trp	missense_variant	Exon 2 of 3	1		ENSP00000380525.2	P56539
CAV3	ENST00000472766.1 link	n.155+11637C>G		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00137

AC:

343

AN:

251078

Hom.:

AF XY:

0.00141

AC XY:

192

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00229

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00222

AC:

3252

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

1561

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00183

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00247

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00250

Gnomad4 OTH exome

AF:

0.00238

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152316

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00241

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00174

Hom.:

Bravo

AF:

0.00183

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00112

AC:

136

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:16Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Aug 05, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CAV3 c.216C>G (p.Cys72Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 283742 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 230 fold of the estimated maximal expected allele frequency for a pathogenic variant in CAV3 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.216C>G has been reported in the literature in individuals with Muscular dystrophy, Long QT syndrome, Sudden Arrhythmic Death Syndrome, Dilated cardiomyopathy or Hypertrophic cardiomyopathy (McNally_1998, Arnestad_2007, Vatta_2006, Pugh_2014, Nunn_2015, Rubattu_2016, Sanchez_2016, Minoche_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. In addition, co-occurrences with other pathogenic variants have been reported (MYBPC3 c.1483C>T, p.Arg495Trp; TTN c.69491_69492del, p.Val23164fs) (Rubattu_2016, Minoche_2018), providing supporting evidence for a benign role. At least one publication reports this variant has no impact on protein function (Cai_2009). Ten ClinVar submitters (evaluation after 2014) cites the variant as uncertain significance (3x), likely benign (5x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Dec 07, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3Other:1

Nov 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25630502, 31043699, 27600940, 25783436, 9536092, 23465283, 11251997) -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAV3: BS1, BS2 -

Feb 12, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2012

Leiden Muscular Dystrophy (CAV3)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Caveolinopathy

Uncertain:1Benign:1

Jul 07, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy

Benign:2

Nov 27, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rippling muscle disease 2

Pathogenic:1

Jan 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Elevated circulating creatine kinase concentration;C1832560:Rippling muscle disease 2;C2678485:Long QT syndrome 9;C3280443:Distal myopathy, Tateyama type;C3495498:Hypertrophic cardiomyopathy 1

Uncertain:1

Mar 16, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Long QT syndrome 1

Benign:1

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CAV3-related disorder

Benign:1

Nov 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy

Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype

Benign:1

Sep 07, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

D;D

Eigen

Benign

0.14

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

.;T

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.26

T;T

MetaSVM

Uncertain

0.76

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Pathogenic

0.77

Sift

Benign

0.095

T;T

Sift4G

Uncertain

0.057

T;T

Polyphen

0.50

P;P

Vest4

0.86

MVP

1.0

MPC

1.7

ClinPred

0.067

GERP RS

3.8

Varity_R

0.87

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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