rs10270569

Variant names:

• chr7-116542728-C-T
• rs10270569
• NM_001753.5:c.195+16039C>T

Variant summary

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

The NM_001753.5(CAV1):​c.195+16039C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,186 control chromosomes in the GnomAD database, including 4,270 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 0.23 (4270 hom., cov: 32)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: CAV1 NM_001753.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.512
• Publications: 14 publications found

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]

CAV1 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• partial lipodystrophy, congenital cataracts, and neurodegeneration syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• pulmonary hypertension, primary, 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital generalized lipodystrophy type 3

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, G2P
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000235427 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001753.5. 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
	CAV1	NM_001753.5	MANE Select	c.195+16039C>T		intron	N/A	NP_001744.2
	CAV1	NM_001172895.1		c.102+16039C>T		intron	N/A	NP_001166366.1
	CAV1	NM_001172896.2		c.102+16039C>T		intron	N/A	NP_001166367.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV1	ENST00000341049.7	TSL:1 MANE Select	c.195+16039C>T		intron	N/A	ENSP00000339191.2
	CAV1	ENST00000393467.1	TSL:1	c.102+16039C>T		intron	N/A	ENSP00000377110.1
	CAV1	ENST00000393468.1	TSL:1	c.102+16039C>T		intron	N/A	ENSP00000377111.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34574 AN: 152052 Hom.: 4271 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.248

GnomAD4 exome AF: 0.0625 AC: 1 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 1 AN XY: 12

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0714 AC: 1 AN: 14

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.227 AC: 34581 AN: 152170 Hom.: 4270 Cov.: 32 AF XY: 0.219 AC XY: 16282 AN XY: 74402

African (AFR) AF: 0.234 AC: 9704 AN: 41508

American (AMR) AF: 0.195 AC: 2982 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1219 AN: 3470

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5184

South Asian (SAS) AF: 0.197 AC: 951 AN: 4828

European-Finnish (FIN) AF: 0.132 AC: 1402 AN: 10604

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17372 AN: 67970

Other (OTH) AF: 0.245 AC: 516 AN: 2106

Alfa AF: 0.257 Hom.: 3051

Bravo AF: 0.234

Asia WGS AF: 0.0950 AC: 334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.8
DANN	Benign	0.58
PhyloP100		0.51
Mutation Taster		=95/5	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: rs10270569; hg19: chr7-116182782;