rs146799286

Positions:

• chr17-42404937-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_012232.6(CAVIN1):​c.923A>G​(p.Tyr308Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00206 in 1,614,000 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: CAVIN1 NM_012232.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 4.76

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11685684).
• BP6: Variant 17-42404937-T-C is Benign according to our data. Variant chr17-42404937-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211974.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00119 (181/152192) while in subpopulation NFE AF= 0.0021 (143/67984). AF 95% confidence interval is 0.00182. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAVIN1	NM_012232.6	c.923A>G	p.Tyr308Cys	missense_variant	2/2	ENST00000357037.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAVIN1	ENST00000357037.6	c.923A>G	p.Tyr308Cys	missense_variant	2/2	1	NM_012232.6	P1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00106 AC: 266 AN: 251292 Hom.: 0 AF XY: 0.00100 AC XY: 136 AN XY: 135846

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00215 AC: 3138 AN: 1461808 Hom.: 3 Cov.: 31 AF XY: 0.00209 AC XY: 1519 AN XY: 727212

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00272

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74416

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00108 AC: 131

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2021	This variant is associated with the following publications: (PMID: 32041611, 33111339, 31604776) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 16, 2014

- -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Dec 15, 2017

ACMG criteria: PP3 (5 predictors), BP4 (5 predictors) = VUS -

Congenital generalized lipodystrophy type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

CAVIN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

This 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.29
Sift	Benign	0.093	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.69
MVP		0.89
ClinPred		0.049	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.77

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

Other links and lift over

dbSNP: rs146799286; hg19: chr17-40556955; COSMIC: COSV105827514;