rs9252

Variant names:

• chr17-42402831-G-A
• rs9252
• NM_012232.6:c.*1856C>T

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.*1856C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0691 in 152,418 control chromosomes in the GnomAD database, including 506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (506 hom., cov: 31)
  • Exomes 𝑓: 0.068 (0 hom.)
• Consequence: CAVIN1 NM_012232.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.237
• Publications: 23 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):

• congenital generalized lipodystrophy type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.82).
• BP6: Variant 17-42402831-G-A is Benign according to our data. Variant chr17-42402831-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 323256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.155 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN1	NM_012232.6	MANE Select	c.*1856C>T		3_prime_UTR	Exon 2 of 2	NP_036364.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAVIN1	ENST00000357037.6	TSL:1 MANE Select	c.*1856C>T		3_prime_UTR	Exon 2 of 2	ENSP00000349541.4
	CAVIN1	ENST00000870236.1		c.*1856C>T		3_prime_UTR	Exon 2 of 2	ENSP00000540295.1

Frequencies

GnomAD3 genomes AF: 0.0691 AC: 10514 AN: 152066 Hom.: 506 Cov.: 31

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.0857

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0762

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0872

Gnomad OTH AF: 0.0851

GnomAD4 exome AF: 0.0684 AC: 16 AN: 234 Hom.: 0 Cov.: 0 AF XY: 0.0843 AC XY: 14 AN XY: 166

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

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

East Asian (EAS) AF: 0.0761 AC: 7 AN: 92

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0763 AC: 9 AN: 118

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.0691 AC: 10515 AN: 152184 Hom.: 506 Cov.: 31 AF XY: 0.0714 AC XY: 5314 AN XY: 74392

African (AFR) AF: 0.0182 AC: 755 AN: 41538

American (AMR) AF: 0.0620 AC: 947 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0857 AC: 297 AN: 3466

East Asian (EAS) AF: 0.125 AC: 646 AN: 5162

South Asian (SAS) AF: 0.165 AC: 795 AN: 4830

European-Finnish (FIN) AF: 0.0762 AC: 808 AN: 10610

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0872 AC: 5927 AN: 67974

Other (OTH) AF: 0.0851 AC: 180 AN: 2114

Alfa AF: 0.0785 Hom.: 673

Bravo AF: 0.0649

Asia WGS AF: 0.138 AC: 478 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.82
CADD	Benign	12
DANN	Benign	0.58
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs9252; hg19: chr17-40554849;