3-8733975-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_033337.3(CAV3):c.99C>T(p.Asn33Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,601,170 control chromosomes in the GnomAD database, including 60,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10596 hom., cov: 30)

Exomes 𝑓: 0.25 ( 49671 hom. )

Consequence

CAV3
NM_033337.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: -0.522

Publications

35 publications found

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:

SSUH2 (HGNC:24809): (ssu-2 homolog) Involved in odontogenesis. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SSUH2 Gene-Disease associations (from GenCC):

dentin dysplasia type I
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SSUH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 3-8733975-C-T is Benign according to our data. Variant chr3-8733975-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.522 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAV3	NM_033337.3 link	c.99C>T	p.Asn33Asn	synonymous_variant	Exon 1 of 2	ENST00000343849.3	NP_203123.1	P56539
CAV3	NM_001234.5 link	c.99C>T	p.Asn33Asn	synonymous_variant	Exon 1 of 3		NP_001225.1	P56539

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAV3	ENST00000343849.3 link	c.99C>T	p.Asn33Asn	synonymous_variant	Exon 1 of 2	1	NM_033337.3	ENSP00000341940.2		P56539

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

53036

AN:

151520

Hom.:

10583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.555

Gnomad AMI

AF:

0.312

Gnomad AMR

AF:

0.338

Gnomad ASJ

AF:

0.296

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.282

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.330

GnomAD2 exomes

AF:

0.294

AC:

73767

AN:

250794

AF XY:

0.284

show subpopulations

Gnomad AFR exome

AF:

0.560

Gnomad AMR exome

AF:

0.323

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.397

Gnomad FIN exome

AF:

0.287

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.294

GnomAD4 exome

AF:

0.253

AC:

366328

AN:

1449532

Hom.:

49671

Cov.:

AF XY:

0.251

AC XY:

181175

AN XY:

721672

show subpopulations

African (AFR)

AF:

0.569

AC:

18839

AN:

33100

American (AMR)

AF:

0.325

AC:

14535

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

7800

AN:

26070

East Asian (EAS)

AF:

0.345

AC:

13669

AN:

39620

South Asian (SAS)

AF:

0.210

AC:

18058

AN:

86036

European-Finnish (FIN)

AF:

0.289

AC:

15442

AN:

53346

Middle Eastern (MID)

AF:

0.326

AC:

1868

AN:

5734

European-Non Finnish (NFE)

AF:

0.235

AC:

259179

AN:

1100994

Other (OTH)

AF:

0.282

AC:

16938

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

12121

24242

36362

48483

60604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8868

17736

26604

35472

44340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.350

AC:

53085

AN:

151638

Hom.:

10596

Cov.:

AF XY:

0.348

AC XY:

25812

AN XY:

74076

show subpopulations

African (AFR)

AF:

0.555

AC:

22941

AN:

41316

American (AMR)

AF:

0.338

AC:

5151

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

1027

AN:

3470

East Asian (EAS)

AF:

0.388

AC:

1989

AN:

5122

South Asian (SAS)

AF:

0.213

AC:

1010

AN:

4752

European-Finnish (FIN)

AF:

0.282

AC:

2969

AN:

10522

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.249

AC:

16908

AN:

67914

Other (OTH)

AF:

0.329

AC:

691

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1587

3174

4762

6349

7936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

498

996

1494

1992

2490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.282

Hom.:

14338

Bravo

AF:

0.367

Asia WGS

AF:

0.322

AC:

1121

AN:

3478

EpiCase

AF:

0.253

EpiControl

AF:

0.257

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 11, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 27, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 15, 2012

Leiden Muscular Dystrophy (CAV3)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Limb-Girdle Muscular Dystrophy, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Caveolinopathy

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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). 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. -

Congenital long QT syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 12, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

-0.52

PromoterAI

-0.061

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over