rs201966419

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS1

The NM_001753.5(CAV1):c.500T>C(p.Phe167Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CAV1
NM_001753.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.88

Variant links:

Genes affected

CAV1 (HGNC:1527): (caveolin 1) The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits to the tyrosine kinase FYN, an initiating step in coupling integrins to the Ras-ERK pathway and promoting cell cycle progression. The gene is a tumor suppressor gene candidate and a negative regulator of the Ras-p42/44 mitogen-activated kinase cascade. Caveolin 1 and caveolin 2 are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex. Mutations in this gene have been associated with Berardinelli-Seip congenital lipodystrophy. Alternatively spliced transcripts encode alpha and beta isoforms of caveolin 1.[provided by RefSeq, Mar 2010]

CAV1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.791

BP6

Variant 7-116559250-T-C is Benign according to our data. Variant chr7-116559250-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541324.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000105 (16/152310) while in subpopulation NFE AF= 0.000162 (11/68026). AF 95% confidence interval is 0.0000905. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAV1	NM_001753.5 link	c.500T>C	p.Phe167Ser	missense_variant	Exon 3 of 3	ENST00000341049.7	NP_001744.2	Q03135-1Q2TNI1Q59E85
CAV1	NM_001172895.1 link	c.407T>C	p.Phe136Ser	missense_variant	Exon 3 of 3		NP_001166366.1	A0A024R757Q2TNI1Q59E85
CAV1	NM_001172896.2 link	c.407T>C	p.Phe136Ser	missense_variant	Exon 2 of 2		NP_001166367.1	A0A024R757Q2TNI1Q7Z4F3Q59E85
CAV1	NM_001172897.2 link	c.407T>C	p.Phe136Ser	missense_variant	Exon 3 of 3		NP_001166368.1	A0A024R757Q2TNI1A9XTE5Q59E85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAV1	ENST00000341049.7 link	c.500T>C	p.Phe167Ser	missense_variant	Exon 3 of 3	1	NM_001753.5	ENSP00000339191.2		Q03135-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000838

AC:

AN:

250712

Hom.:

AF XY:

0.0000886

AC XY:

AN XY:

135494

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000150

AC:

219

AN:

1461482

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000168

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000105

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:1

Feb 22, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: PP3 (REVEL 0.9 + 10 predictors) = VUS -

not provided

Uncertain:1

Aug 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as c.407 T>C p.(Phe136Ser) due to use of alternate nomenclature in individuals with pulmonary arterial hypertension (Zhu et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33264630, 32041611, 31727138) -

Congenital generalized lipodystrophy type 3;C3807567:Partial lipodystrophy, congenital cataracts, and neurodegeneration syndrome;C3809192:Pulmonary hypertension, primary, 3

Benign:1

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pulmonary hypertension, primary, 3

Benign:1

Jun 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.;.;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D;.;T;.;.

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.7

M;.;.;.;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.0

D;D;.;D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0050

D;D;.;D;D;D;D

Sift4G

Uncertain

0.051

T;T;T;T;D;T;T

Polyphen

0.99

D;.;.;.;.;.;.

Vest4

0.74

MVP

1.0

MPC

2.0

ClinPred

0.89

GERP RS

5.6

Varity_R

0.91

gMVP

0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over