rs4796583

Variant names:

• chr17-42403241-C-G
• rs4796583
• NM_012232.6:c.*1446G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.39
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• lipodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital generalized lipodystrophy type 4

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012232.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN1	NM_012232.6	MANE Select	c.*1446G>C		3_prime_UTR	Exon 2 of 2	NP_036364.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN1	ENST00000357037.6	TSL:1 MANE Select	c.*1446G>C		3_prime_UTR	Exon 2 of 2	ENSP00000349541.4	Q6NZI2-1
	CAVIN1	ENST00000870236.1		c.*1446G>C		3_prime_UTR	Exon 2 of 2	ENSP00000540295.1

Frequencies

GnomAD3 genomes AF: 0.0446 AC: 6787 AN: 152028 Hom.: 225 Cov.: 31

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: 24 AN: 316 Hom.: 0 Cov.: 0 AF XY: 0.0748 AC XY: 16 AN XY: 214

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.0741 AC: 8 AN: 108

South Asian (SAS) AF: 0.00 AC: 0 AN: 8

European-Finnish (FIN) AF: 0.0500 AC: 2 AN: 40

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0903 AC: 13 AN: 144

Other (OTH) AF: 0.100 AC: 1 AN: 10

GnomAD4 genome AF: 0.0446 AC: 6787 AN: 152146 Hom.: 225 Cov.: 31 AF XY: 0.0429 AC XY: 3189 AN XY: 74392

African (AFR) AF: 0.0124 AC: 514 AN: 41532

American (AMR) AF: 0.0721 AC: 1101 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0609 AC: 211 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4828

European-Finnish (FIN) AF: 0.0195 AC: 207 AN: 10602

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0653 AC: 4437 AN: 67966

Other (OTH) AF: 0.0721 AC: 152 AN: 2108

Alfa AF: 0.0515 Hom.: 35

Bravo AF: 0.0479

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital generalized lipodystrophy type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.5
DANN	Benign	0.67
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs4796583; hg19: chr17-40555259;