3-8745644-C-T

Variant names:

• chr3-8745644-C-T
• rs72546668
• NM_033337.3:c.233C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_033337.3(CAV3):​c.233C>T​(p.Thr78Met) variant causes a missense change. The variant allele was found at a frequency of 0.00249 in 1,614,100 control chromosomes in the GnomAD database, including 8 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. T78K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6 B:16 O:1
• Conservation: PhyloP100: 3.78
• Publications: 60 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 -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain 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=0.017467082).
• BP6: Variant 3-8745644-C-T is Benign according to our data. Variant chr3-8745644-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8293.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00301 (459/152316) while in subpopulation AFR AF = 0.00337 (140/41574). AF 95% confidence interval is 0.00294. There are 2 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.233C>T	p.Thr78Met	missense	Exon 2 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.233C>T	p.Thr78Met	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.233C>T	p.Thr78Met	missense	Exon 2 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.233C>T	p.Thr78Met	missense	Exon 2 of 3	ENSP00000380525.2	P56539
	CAV3	ENST00000472766.1	TSL:2	n.155+11654C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 458 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00263 AC: 660 AN: 250926 AF XY: 0.00262

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00243 AC: 3559 AN: 1461784 Hom.: 6 Cov.: 32 AF XY: 0.00243 AC XY: 1764 AN XY: 727178

African (AFR) AF: 0.00355 AC: 119 AN: 33480

American (AMR) AF: 0.000939 AC: 42 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86226

European-Finnish (FIN) AF: 0.00303 AC: 162 AN: 53404

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.00257 AC: 2863 AN: 1111966

Other (OTH) AF: 0.00267 AC: 161 AN: 60394

GnomAD4 genome AF: 0.00301 AC: 459 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74484

African (AFR) AF: 0.00337 AC: 140 AN: 41574

American (AMR) AF: 0.00118 AC: 18 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00480 AC: 51 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00329 AC: 224 AN: 68018

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00332 Hom.: 4

Bravo AF: 0.00293

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	5	not specified (7)
-	-	4	not provided (5)
-	1	2	Long QT syndrome (3)
-	-	2	Cardiomyopathy (2)
1	1	-	Long QT syndrome 9 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	CAV3-related disorder (1)
-	1	-	Caveolinopathy (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	-	1	Long QT syndrome 1 (1)
1	-	-	Long QT syndrome 2/9, digenic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.83	N
REVEL	Pathogenic	0.65
Sift	Benign	0.076	T
Sift4G	Uncertain	0.055	T
Polyphen		0.97	D
Vest4		0.27
MVP		0.99
MPC		1.0
ClinPred		0.063	T
GERP RS		4.6
Varity_R		0.52
gMVP		0.74
Mutation Taster		=41/59	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: rs72546668; hg19: chr3-8787330; COSMIC: COSV57479098; COSMIC: COSV57479098;