rs12948909

Variant names:

• chr17-42418584-A-C
• rs12948909
• NM_012232.6:c.471+4043T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012232.6(CAVIN1):​c.471+4043T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 151,988 control chromosomes in the GnomAD database, including 4,820 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4820 hom., cov: 31)
• Consequence: CAVIN1 NM_012232.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.805
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAVIN1	NM_012232.6	c.471+4043T>G		intron_variant	Intron 1 of 1	ENST00000357037.6	NP_036364.2
CAVIN1	XM_005257242.5	c.471+4043T>G		intron_variant	Intron 1 of 1		XP_005257299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAVIN1	ENST00000357037.6	c.471+4043T>G		intron_variant	Intron 1 of 1	1	NM_012232.6	ENSP00000349541.4

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37159 AN: 151870 Hom.: 4806 Cov.: 31

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.251

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.245 AC: 37209 AN: 151988 Hom.: 4820 Cov.: 31 AF XY: 0.247 AC XY: 18350 AN XY: 74286

African (AFR) AF: 0.264 AC: 10938 AN: 41434

American (AMR) AF: 0.184 AC: 2809 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 552 AN: 3468

East Asian (EAS) AF: 0.106 AC: 550 AN: 5178

South Asian (SAS) AF: 0.409 AC: 1975 AN: 4824

European-Finnish (FIN) AF: 0.268 AC: 2834 AN: 10558

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16728 AN: 67960

Other (OTH) AF: 0.256 AC: 540 AN: 2106

Alfa AF: 0.232 Hom.: 1899

Bravo AF: 0.236

Asia WGS AF: 0.311 AC: 1083 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.8
DANN	Benign	0.66
PhyloP100		0.81
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: rs12948909; hg19: chr17-40570602;