rs61729285

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_012232.6(CAVIN1):​c.65C>T​(p.Pro22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,611,430 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

CAVIN1
NM_012232.6 missense

Scores

2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.91
Variant links:
Genes affected
CAVIN1 (HGNC:9688): (caveolae associated protein 1) This gene encodes a protein that enables the dissociation of paused ternary polymerase I transcription complexes from the 3' end of pre-rRNA transcripts. This protein regulates rRNA transcription by promoting the dissociation of transcription complexes and the reinitiation of polymerase I on nascent rRNA transcripts. This protein also localizes to caveolae at the plasma membrane and is thought to play a critical role in the formation of caveolae and the stabilization of caveolins. This protein translocates from caveolae to the cytoplasm after insulin stimulation. Caveolae contain truncated forms of this protein and may be the site of phosphorylation-dependent proteolysis. This protein is also thought to modify lipid metabolism and insulin-regulated gene expression. Mutations in this gene result in a disorder characterized by generalized lipodystrophy and muscular dystrophy. [provided by RefSeq, Nov 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.005233854).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00101 (154/152270) while in subpopulation AFR AF= 0.00306 (127/41540). AF 95% confidence interval is 0.00263. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CAVIN1NM_012232.6 linkuse as main transcriptc.65C>T p.Pro22Leu missense_variant 1/2 ENST00000357037.6 NP_036364.2 Q6NZI2-1
CAVIN1XM_005257242.5 linkuse as main transcriptc.65C>T p.Pro22Leu missense_variant 1/2 XP_005257299.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CAVIN1ENST00000357037.6 linkuse as main transcriptc.65C>T p.Pro22Leu missense_variant 1/21 NM_012232.6 ENSP00000349541.4 Q6NZI2-1

Frequencies

GnomAD3 genomes
AF:
0.000986
AC:
150
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00299
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.000217
AC:
52
AN:
239818
Hom.:
0
AF XY:
0.000167
AC XY:
22
AN XY:
131690
show subpopulations
Gnomad AFR exome
AF:
0.00277
Gnomad AMR exome
AF:
0.000205
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000990
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000188
Gnomad OTH exome
AF:
0.000169
GnomAD4 exome
AF:
0.000115
AC:
168
AN:
1459160
Hom.:
1
Cov.:
32
AF XY:
0.000103
AC XY:
75
AN XY:
725840
show subpopulations
Gnomad4 AFR exome
AF:
0.00263
Gnomad4 AMR exome
AF:
0.000495
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000105
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.000664
GnomAD4 genome
AF:
0.00101
AC:
154
AN:
152270
Hom.:
0
Cov.:
32
AF XY:
0.000967
AC XY:
72
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.00306
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.000291
Hom.:
0
Bravo
AF:
0.00126
ESP6500AA
AF:
0.00261
AC:
11
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.000307
AC:
37

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 29, 2023The c.65C>T (p.P22L) alteration is located in exon 1 (coding exon 1) of the PTRF gene. This alteration results from a C to T substitution at nucleotide position 65, causing the proline (P) at amino acid position 22 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitterresearchPersonalized Diabetes Medicine Program, University of Maryland School of MedicineFeb 17, 2017ACMG Criteria:BP4 (9 predictors) -
Congenital generalized lipodystrophy type 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityFeb 19, 2020- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2019- -
CAVIN1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 27, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.0052
T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.11
Sift
Uncertain
0.0060
D
Sift4G
Benign
0.16
T
Polyphen
0.0
B
Vest4
0.068
MVP
0.64
ClinPred
0.090
T
GERP RS
1.0
Varity_R
0.036
gMVP
0.30

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.

Other links and lift over

dbSNP: rs61729285; hg19: chr17-40575051; API