NM_033337.3:c.166G>A

Variant names:

• chr3-8745577-G-A
• rs72546667
• NM_033337.3:c.166G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:21 O:1
• Conservation: PhyloP100: 7.70
• Publications: 16 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: Benign. The variant received -17 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
• 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.
• 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 Benign/Likely_benign. ClinVar VariationId is 8278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	NM_033337.3	MANE Select	c.166G>A	p.Gly56Ser	missense	Exon 2 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.166G>A	p.Gly56Ser	missense	Exon 2 of 3	NP_001225.1	P56539

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	ENST00000343849.3	TSL:1 MANE Select	c.166G>A	p.Gly56Ser	missense	Exon 2 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.166G>A	p.Gly56Ser	missense	Exon 2 of 3	ENSP00000380525.2	P56539
	CAV3	ENST00000472766.1	TSL:2	n.155+11587G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5021 AN: 152078 Hom.: 264 Cov.: 32

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

GnomAD2 exomes AF: 0.00888 AC: 2233 AN: 251334 AF XY: 0.00640

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 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.: 32 AF XY: 0.00321 AC XY: 2333 AN XY: 727226

African (AFR) AF: 0.121 AC: 4049 AN: 33472

American (AMR) AF: 0.00742 AC: 332 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00694 AC: 40 AN: 5766

European-Non Finnish (NFE) AF: 0.000270 AC: 300 AN: 1111990

Other (OTH) AF: 0.00907 AC: 548 AN: 60396

GnomAD4 genome AF: 0.0331 AC: 5036 AN: 152196 Hom.: 266 Cov.: 32 AF XY: 0.0317 AC XY: 2356 AN XY: 74416

African (AFR) AF: 0.114 AC: 4713 AN: 41514

American (AMR) AF: 0.0154 AC: 235 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68002

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.00919 Hom.: 255

Bravo AF: 0.0377

ESP6500AA AF: 0.109 AC: 481

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0107 AC: 1298

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (5)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Caveolinopathy (1)
-	-	1	Elevated circulating creatine kinase concentration;C1832560:Rippling muscle disease 2;C2678485:Long QT syndrome 9;C3280443:Distal myopathy, Tateyama type;C3495498:Hypertrophic cardiomyopathy 1 (1)
-	-	1	Limb-girdle muscular dystrophy (1)
-	-	1	Limb-Girdle Muscular Dystrophy, Dominant (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 1 (1)
-	1	-	Rippling muscle disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.022	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.28
MPC		1.5
ClinPred		0.029	T
GERP RS		3.7
Varity_R		0.64
gMVP		0.85
Mutation Taster		=50/50	polymorphism (auto)

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: rs72546667; hg19: chr3-8787263; COSMIC: COSV57481688; COSMIC: COSV57481688;