Genetic Variant CAVIN3:p.Leu255Ile (chr11-6319186-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145040.3(CAVIN3):c.763C>A(p.Leu255Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,384,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CAVIN3
NM_145040.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.35

Publications

0 publications found

Variant links:

Genes affected

CAVIN3 (HGNC:9400): (caveolae associated protein 3) The protein encoded by this gene was identified as a binding protein of the protein kinase C, delta (PRKCD). The expression of this gene in cultured cell lines is strongly induced by serum starvation. The expression of this protein was found to be down-regulated in various cancer cell lines, suggesting the possible tumor suppressor function of this protein. [provided by RefSeq, Jul 2008]

CAVIN3 links:

ENSG00000282556 (HGNC:):

ENSG00000282556 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2284303).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145040.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN3	NM_145040.3	MANE Select	c.763C>A	p.Leu255Ile	missense	Exon 2 of 2	NP_659477.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAVIN3	ENST00000303927.4	TSL:1 MANE Select	c.763C>A	p.Leu255Ile	missense	Exon 2 of 2	ENSP00000307292.3
CAVIN3	ENST00000530979.1	TSL:2	c.859C>A	p.Leu287Ile	missense	Exon 3 of 3	ENSP00000432047.1
CAVIN3	ENST00000524852.1	TSL:3	n.549C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1384796

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

681824

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30668

American (AMR)

AF:

0.00

AC:

AN:

31300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20558

East Asian (EAS)

AF:

0.00

AC:

AN:

38990

South Asian (SAS)

AF:

0.00

AC:

AN:

72534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077874

Other (OTH)

AF:

0.00

AC:

AN:

56966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.065

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.37

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.77

PhyloP100

2.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.22

REVEL

Benign

0.096

Sift

Uncertain

0.019

Sift4G

Pathogenic

0.0

Polyphen

0.62

Vest4

0.28

MutPred

0.24

Loss of phosphorylation at S259 (P = 0.1842)

MVP

0.38

MPC

0.42

ClinPred

0.67

GERP RS

5.1

Varity_R

0.14

gMVP

0.041

Mutation Taster

=90/10

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over