7-116500297-C-A

Position:

• chr7-116500297-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001233.5(CAV2):​c.188C>A​(p.Thr63Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CAV2 NM_001233.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

Genes affected

CAV2 (HGNC:1528): (caveolin 2) The protein encoded by this gene is a major component of the inner surface of caveolae, small invaginations of the plasma membrane, and is involved in essential cellular functions, including signal transduction, lipid metabolism, cellular growth control and apoptosis. This protein may function as a tumor suppressor. This gene and related family member (CAV1) are located next to each other on chromosome 7, and express colocalizing proteins that form a stable hetero-oligomeric complex. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. Additional isoforms resulting from the use of alternate in-frame translation initiation codons have also been described, and shown to have preferential localization in the cell (PMID:11238462). [provided by RefSeq, May 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAV2	NM_001233.5	c.188C>A	p.Thr63Lys	missense_variant	2/3	ENST00000222693.5	NP_001224.1
CAV2	NM_001206747.2	c.149C>A	p.Thr50Lys	missense_variant	2/3		NP_001193676.1
CAV2	NM_001206748.2	c.-62C>A		5_prime_UTR_variant	1/2		NP_001193677.1
CAV2	NM_198212.3	c.150+366C>A		intron_variant			NP_937855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAV2	ENST00000222693.5	c.188C>A	p.Thr63Lys	missense_variant	2/3	1	NM_001233.5	ENSP00000222693.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461862 Hom.: 0 Cov.: 38 AF XY: 0.0000110 AC XY: 8 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.188C>A (p.T63K) alteration is located in exon 2 (coding exon 2) of the CAV2 gene. This alteration results from a C to A substitution at nucleotide position 188, causing the threonine (T) at amino acid position 63 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Benign	-0.0028
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.32	B;.
Vest4		0.77
MutPred		0.62		Gain of ubiquitination at T63 (P = 0.0198);Gain of ubiquitination at T63 (P = 0.0198);
MVP		0.92
MPC		1.1
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1355914850; hg19: chr7-116140351;