rs72546667

Positions:

chr3-8745577-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_033337.3(CAV3):c.166G>A(p.Gly56Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,614,038 control chromosomes in the GnomAD database, including 549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G56G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.033 ( 266 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 283 hom. )

Consequence

CAV3
NM_033337.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:20O:1

Conservation

PhyloP100: 7.70

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:):

OXTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 61 pathogenic changes around while only 13 benign (82%) in NM_033337.3

BP4

Computational evidence support a benign effect (MetaRNN=0.005708784).

BP6

Variant 3-8745577-G-A is Benign according to our data. Variant chr3-8745577-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 8278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-8745577-G-A is described in Lovd as [Pathogenic]. Variant chr3-8745577-G-A is described in Lovd as [Benign]. Variant chr3-8745577-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-8745577-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAV3	NM_033337.3 linkuse as main transcript	c.166G>A	p.Gly56Ser	missense_variant	2/2	ENST00000343849.3
CAV3	NM_001234.5 linkuse as main transcript	c.166G>A	p.Gly56Ser	missense_variant	2/3
OXTR	XR_007095681.1 linkuse as main transcript	n.1885-2975C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CAV3	ENST00000343849.3 linkuse as main transcript	c.166G>A	p.Gly56Ser	missense_variant	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2 linkuse as main transcript	c.166G>A	p.Gly56Ser	missense_variant	2/3	1		P1
CAV3	ENST00000472766.1 linkuse as main transcript	n.155+11587G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0330

AC:

5021

AN:

152078

Hom.:

264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.00888

AC:

2233

AN:

251334

Hom.:

140

AF XY:

0.00640

AC XY:

869

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.00613

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00366

AC:

5357

AN:

1461842

Hom.:

283

Cov.:

AF XY:

0.00321

AC XY:

2333

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.121

Gnomad4 AMR exome

AF:

0.00742

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.000893

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000270

Gnomad4 OTH exome

AF:

0.00907

GnomAD4 genome

AF:

0.0331

AC:

5036

AN:

152196

Hom.:

266

Cov.:

AF XY:

0.0317

AC XY:

2356

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.114

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.00701

Hom.:

100

Bravo

AF:

0.0377

ESP6500AA

AF:

0.109

AC:

481

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0107

AC:

1298

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 10, 2012	Gly56Ser in exon 2 of CAV3: This variant is not expected to have clinical signif icance because it has been identified in 10.9% (407/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/; dbSNP rs72546667) -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (CAV3)	-	- -

Rippling muscle disease 2

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Long QT syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Limb-Girdle Muscular Dystrophy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 31, 2020

- -

Caveolinopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Limb-girdle muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2015

This alteration is classified as 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

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.022

D;D

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;D

Vest4

0.28

MPC

1.5

ClinPred

0.029

GERP RS

3.7

Varity_R

0.64

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