3-8733960-C-A

Position:

• chr3-8733960-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_033337.3(CAV3):​c.84C>A​(p.Asp28Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.17

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]

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

ACMG classification

Verdict is Likely_pathogenic. 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-8733960-C-A is Pathogenic according to our data. Variant chr3-8733960-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 8280.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-8733960-C-A is described in Lovd as [Pathogenic]. Variant chr3-8733960-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAV3	NM_033337.3	c.84C>A	p.Asp28Glu	missense_variant	1/2	ENST00000343849.3	NP_203123.1
CAV3	NM_001234.5	c.84C>A	p.Asp28Glu	missense_variant	1/3		NP_001225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAV3	ENST00000343849.3	c.84C>A	p.Asp28Glu	missense_variant	1/2	1	NM_033337.3	ENSP00000341940	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Rippling muscle disease 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (CAV3)

Apr 15, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.97		Gain of ubiquitination at K30 (P = 0.0931);Gain of ubiquitination at K30 (P = 0.0931);
MVP		1.0
MPC		0.83
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.92
gMVP		0.96

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

Other links and lift over

dbSNP: rs116840782; hg19: chr3-8775646;