rs10029

Positions:

• chr7-116526650-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The ENST00000614113.5(CAV1):​c.334C>T​(p.Gln112Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,614,128 control chromosomes in the GnomAD database, including 518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (295 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (223 hom.)
• Consequence: CAV1 ENST00000614113.5 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.02

Genes affected

CAV1 (HGNC:1527): (caveolin 1) The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits to the tyrosine kinase FYN, an initiating step in coupling integrins to the Ras-ERK pathway and promoting cell cycle progression. The gene is a tumor suppressor gene candidate and a negative regulator of the Ras-p42/44 mitogen-activated kinase cascade. Caveolin 1 and caveolin 2 are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex. Mutations in this gene have been associated with Berardinelli-Seip congenital lipodystrophy. Alternatively spliced transcripts encode alpha and beta isoforms of caveolin 1.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0402 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 7-116526650-C-T is Benign according to our data. Variant chr7-116526650-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116526650-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV1	NM_001753.5	c.156C>T	p.Val52=	synonymous_variant	2/3	ENST00000341049.7
CAV1	NM_001172895.1	c.63C>T	p.Val21=	synonymous_variant	2/3
CAV1	NM_001172896.2	c.63C>T	p.Val21=	synonymous_variant	1/2
CAV1	NM_001172897.2	c.63C>T	p.Val21=	synonymous_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV1	ENST00000341049.7	c.156C>T	p.Val52=	synonymous_variant	2/3	1	NM_001753.5	P3

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5184 AN: 152160 Hom.: 295 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.00890 AC: 2238 AN: 251354 Hom.: 124 AF XY: 0.00651 AC XY: 884 AN XY: 135870

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00345 AC: 5037 AN: 1461850 Hom.: 223 Cov.: 32 AF XY: 0.00292 AC XY: 2123 AN XY: 727220

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.00751

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.00752

GnomAD4 genome AF: 0.0341 AC: 5195 AN: 152278 Hom.: 295 Cov.: 32 AF XY: 0.0327 AC XY: 2435 AN XY: 74470

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0140 Hom.: 54

Bravo AF: 0.0384

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Pulmonary hypertension, primary, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Benign	0.96

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

Other links and lift over

dbSNP: rs10029; hg19: chr7-116166704; COSMIC: COSV61952807;