Genetic Variant CAVIN3:p.Arg59His (chr11-6320301-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_145040.3(CAVIN3):c.176G>A(p.Arg59His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Uncertain significance.

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: 1.23

Publications

3 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31454697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAVIN3	NM_145040.3 link	c.176G>A	p.Arg59His	missense_variant	Exon 1 of 2	ENST00000303927.4	NP_659477.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAVIN3	ENST00000303927.4 link	c.176G>A	p.Arg59His	missense_variant	Exon 1 of 2	1	NM_145040.3	ENSP00000307292.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1412742

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700554

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:

32410

American (AMR)

AF:

0.0000251

AC:

AN:

39856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25458

East Asian (EAS)

AF:

0.00

AC:

AN:

37368

South Asian (SAS)

AF:

0.00

AC:

AN:

82086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095024

Other (OTH)

AF:

0.00

AC:

AN:

58858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.056

T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.85

T;D

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.56

PhyloP100

1.2

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.12

Sift

Benign

0.032

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.26

MutPred

0.27

Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);

MVP

0.62

MPC

1.2

ClinPred

0.95

GERP RS

5.0

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.22

gMVP

0.095

Mutation Taster

=84/16

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over