rs116840776

chr3-8745627-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C72Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (8 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:16 O:1
• Conservation: PhyloP100: 1.13

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]

OXTR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 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=0.26156944).
• 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: {Benign=6, Uncertain_significance=1, Likely_benign=10, 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 GnomAd at 256 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.216C>G	p.Cys72Trp	missense_variant	2/2	ENST00000343849.3
CAV3	NM_001234.5	c.216C>G	p.Cys72Trp	missense_variant	2/3
OXTR	XR_007095681.1	n.1885-3025G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.216C>G	p.Cys72Trp	missense_variant	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2	c.216C>G	p.Cys72Trp	missense_variant	2/3	1		P1
CAV3	ENST00000472766.1	n.155+11637C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152198 Hom.: 2 Cov.: 32

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.: 1 AF XY: 0.00141 AC XY: 192 AN XY: 135698

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.: 8 Cov.: 32 AF XY: 0.00215 AC XY: 1561 AN XY: 727202

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.: 2 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74488

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.: 0

Bravo AF: 0.00183

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00112 AC: 136

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2018	proposed classification - variant undergoing re-assessment, contact laboratory -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 23, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2020	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. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 07, 2016	- -

not provided Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 25630502, 31043699, 27600940, 25783436, 9536092, 23465283, 11251997) -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (CAV3)	Apr 15, 2012	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	CAV3: BS1, BS2 -

Caveolinopathy Uncertain:1 Benign:1

Uncertain significance, 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). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jul 07, 2023	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Mar 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 27, 2019	- -

Rippling muscle disease 2 Pathogenic:1

Pathogenic, 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 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Mar 16, 2016

- -

Long QT syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

CAV3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Limb-girdle muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2018

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	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Benign	0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.67	T
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	T
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

Other links and lift over

dbSNP: rs116840776; hg19: chr3-8787313;