chr3-8745655-G-A

Variant names:

• chr3-8745655-G-A
• rs112626848
• NM_033337.3:c.244G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4 BS1

The NM_033337.3(CAV3):​c.244G>A​(p.Val82Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. V82A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 3.43
• Publications: 10 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_benign. The variant received -2 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, 19 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 distal myopathy, Tateyama type, caveolinopathy, inherited rippling muscle disease, autosomal dominant limb-girdle muscular dystrophy type 1C, long QT syndrome, long QT syndrome 9, Brugada syndrome, rippling muscle disease 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2919835).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000722 (11/152286) while in subpopulation AMR AF = 0.000196 (3/15292). AF 95% confidence interval is 0.0000627. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.244G>A	p.Val82Ile	missense	Exon 2 of 2	NP_203123.1	P56539
	CAV3	NM_001234.5		c.244G>A	p.Val82Ile	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.244G>A	p.Val82Ile	missense	Exon 2 of 2	ENSP00000341940.2	P56539
	CAV3	ENST00000397368.2	TSL:1	c.244G>A	p.Val82Ile	missense	Exon 2 of 3	ENSP00000380525.2	P56539
	CAV3	ENST00000472766.1	TSL:2	n.155+11665G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000956 AC: 24 AN: 250942 AF XY: 0.000118

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 727174

African (AFR) AF: 0.000388 AC: 13 AN: 33478

American (AMR) AF: 0.000291 AC: 13 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000156 AC: 173 AN: 1111958

Other (OTH) AF: 0.000497 AC: 30 AN: 60388

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74452

African (AFR) AF: 0.000144 AC: 6 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	-	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)
-	1	-	Long QT syndrome 1 (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.64
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	-1.3	N
PhyloP100		3.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.35
MVP		0.47
MPC		0.43
ClinPred		0.025	T
GERP RS		2.8
Varity_R		0.042
gMVP		0.51
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs112626848; hg19: chr3-8787341; COSMIC: COSV57479298; COSMIC: COSV57479298;