3-8745583-T-C

Variant names:

• chr3-8745583-T-C
• rs199476330
• NM_033337.3:c.172T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_033337.3(CAV3):​c.172T>C​(p.Trp58Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W58G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.61
• Publications: 0 publications found

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: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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 14 pathogenic changes around while only 6 benign (70%) in NM_033337.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.83011 (below the threshold of 3.09). Trascript score misZ: 0.9876 (below the threshold of 3.09). GenCC associations: The gene is linked to rippling muscle disease 2, hypertrophic cardiomyopathy 1, long QT syndrome 9, distal myopathy, Tateyama type, inherited rippling muscle disease, Brugada syndrome, autosomal dominant limb-girdle muscular dystrophy type 1C, caveolinopathy, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033337.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	NM_033337.3	MANE Select	c.172T>C	p.Trp58Arg	missense	Exon 2 of 2	NP_203123.1
	CAV3	NM_001234.5		c.172T>C	p.Trp58Arg	missense	Exon 2 of 3	NP_001225.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	ENST00000343849.3	TSL:1 MANE Select	c.172T>C	p.Trp58Arg	missense	Exon 2 of 2	ENSP00000341940.2
	CAV3	ENST00000397368.2	TSL:1	c.172T>C	p.Trp58Arg	missense	Exon 2 of 3	ENSP00000380525.2
	CAV3	ENST00000472766.1	TSL:2	n.155+11593T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

Apr 15, 2012

Leiden Muscular Dystrophy (CAV3)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-14	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.96		Gain of methylation at W58 (P = 0.0229)
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.98
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs199476330; hg19: chr3-8787269;