17-42403179-C-T

Variant names:

• chr17-42403179-C-T
• rs117596331
• NM_012232.6:c.*1508G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012232.6(CAVIN1):​c.*1508G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 152,240 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAVIN1 NM_012232.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.113
• Publications: 2 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=-0.83).
• BP6: Variant 17-42403179-C-T is Benign according to our data. Variant chr17-42403179-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 323261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00517 (787/152240) while in subpopulation NFE AF = 0.0091 (619/68010). AF 95% confidence interval is 0.00851. There are 6 homozygotes in GnomAd4. There are 353 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.*1508G>A		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.*1508G>A		3_prime_UTR	Exon 2 of 2	ENSP00000349541.4	Q6NZI2-1
	CAVIN1	ENST00000870236.1		c.*1508G>A		3_prime_UTR	Exon 2 of 2	ENSP00000540295.1

Frequencies

GnomAD3 genomes AF: 0.00518 AC: 788 AN: 152122 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.00527

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 410 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 332

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 22

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 344

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

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152240 Hom.: 6 Cov.: 31 AF XY: 0.00474 AC XY: 353 AN XY: 74428

African (AFR) AF: 0.00159 AC: 66 AN: 41550

American (AMR) AF: 0.00399 AC: 61 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10598

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00910 AC: 619 AN: 68010

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00566 Hom.: 2

Bravo AF: 0.00516

Asia WGS AF: 0.0100 AC: 36 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	-0.83
CADD	Benign	6.2
DANN	Benign	0.68
PhyloP100		0.11
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: rs117596331; hg19: chr17-40555197;