chr7-116499795-C-A

Variant names:

• chr7-116499795-C-A
• rs762827815
• NM_001233.5:c.14C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001233.5(CAV2):​c.14C>A​(p.Thr5Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,424,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAV2 NM_001233.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• Publications: 0 publications found

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]

CAV2 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27269733).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001233.5. 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
	CAV2	NM_001233.5	MANE Select	c.14C>A	p.Thr5Lys	missense	Exon 1 of 3	NP_001224.1	Q53X57
	CAV2	NM_198212.3		c.14C>A	p.Thr5Lys	missense	Exon 1 of 2	NP_937855.1	P51636-3
	CAV2	NM_001206747.2		c.-26C>A		5_prime_UTR	Exon 1 of 3	NP_001193676.1	P51636-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV2	ENST00000222693.5	TSL:1 MANE Select	c.14C>A	p.Thr5Lys	missense	Exon 1 of 3	ENSP00000222693.4	P51636-1
	CAV2	ENST00000343213.2	TSL:1	c.14C>A	p.Thr5Lys	missense	Exon 1 of 2	ENSP00000345679.2	P51636-3
	CAV2	ENST00000462876.5	TSL:1	n.1320-46C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1424768 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 705794

African (AFR) AF: 0.00 AC: 0 AN: 32084

American (AMR) AF: 0.00 AC: 0 AN: 38756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25050

East Asian (EAS) AF: 0.00 AC: 0 AN: 37312

South Asian (SAS) AF: 0.00 AC: 0 AN: 81198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095808

Other (OTH) AF: 0.0000169 AC: 1 AN: 59112

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.6	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.32
Sift	Benign	0.53	T
Sift4G	Benign	0.83	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.30		Gain of ubiquitination at K5 (P = 0.0048)
MVP		0.95
MPC		0.46
ClinPred		0.62	D
GERP RS		1.1
PromoterAI		-0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.078
gMVP		0.20
Mutation Taster		=78/22	polymorphism

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: rs762827815; hg19: chr7-116139849;