Genetic Variant NM_012232.6:c.*1446G>C (chr17-42403241-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012232.6(CAVIN1):c.*1446G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0447 in 152,462 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 225 hom., cov: 31)

Exomes 𝑓: 0.076 ( 0 hom. )

Consequence

CAVIN1
NM_012232.6 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.39

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]

CAVIN1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 17-42403241-C-G is Benign according to our data. Variant chr17-42403241-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 323263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAVIN1	NM_012232.6 link	c.*1446G>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000357037.6	NP_036364.2	Q6NZI2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAVIN1	ENST00000357037 link	c.*1446G>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_012232.6	ENSP00000349541.4		Q6NZI2-1

Frequencies

GnomAD3 genomes

AF:

0.0446

AC:

6787

AN:

152028

Hom.:

225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0124

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.0721

Gnomad ASJ

AF:

0.0609

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.0195

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0653

Gnomad OTH

AF:

0.0729

GnomAD4 exome

AF:

0.0759

AC:

AN:

316

Hom.:

Cov.:

AF XY:

0.0748

AC XY:

AN XY:

214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0741

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0500

Gnomad4 NFE exome

AF:

0.0903

Gnomad4 OTH exome

AF:

0.100

GnomAD4 genome

AF:

0.0446

AC:

6787

AN:

152146

Hom.:

225

Cov.:

AF XY:

0.0429

AC XY:

3189

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0124

Gnomad4 AMR

AF:

0.0721

Gnomad4 ASJ

AF:

0.0609

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0108

Gnomad4 FIN

AF:

0.0195

Gnomad4 NFE

AF:

0.0653

Gnomad4 OTH

AF:

0.0721

Alfa

AF:

0.0515

Hom.:

Bravo

AF:

0.0479

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital generalized lipodystrophy type 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.5

DANN

Benign

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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