Genetic Variant CAV1:c.30+28C>T (chr7-116525120-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001172895.1(CAV1):c.-749C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,614,140 control chromosomes in the GnomAD database, including 873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 39 hom., cov: 33)

Exomes 𝑓: 0.032 ( 834 hom. )

Consequence

CAV1
NM_001172895.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.24

Publications

7 publications found

Variant links:

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
congenital generalized lipodystrophy type 3
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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
lipodystrophy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CAV1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 7-116525120-C-T is Benign according to our data. Variant chr7-116525120-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1211194.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 = 0.0226 (3443/152290) while in subpopulation NFE AF = 0.0351 (2386/68030). AF 95% confidence interval is 0.0339. There are 39 homozygotes in GnomAd4. There are 1642 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172895.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CAV1	NM_001753.5	MANE Select	c.30+28C>T	intron	N/A	NP_001744.2
CAV1	NM_001172895.1		c.-749C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001166366.1	Q59E85
CAV1	NM_001172895.1		c.-749C>T	5_prime_UTR	Exon 1 of 3	NP_001166366.1	Q59E85

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CAV1	ENST00000341049.7	TSL:1 MANE Select	c.30+28C>T	intron	N/A	ENSP00000339191.2	Q03135-1
CAV1	ENST00000614113.5	TSL:1	c.30+28C>T	intron	N/A	ENSP00000479447.2	A0A7P0YWJ6
CAV1	ENST00000451122.5	TSL:1	n.58C>T	non_coding_transcript_exon	Exon 1 of 3	ENSP00000409541.1	F8WDM7

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

3440

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00784

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0298

Gnomad FIN

AF:

0.0167

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0231

AC:

5771

AN:

249554

AF XY:

0.0246

show subpopulations

Gnomad AFR exome

AF:

0.00661

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0169

Gnomad NFE exome

AF:

0.0334

Gnomad OTH exome

AF:

0.0255

GnomAD4 exome

AF:

0.0315

AC:

46116

AN:

1461850

Hom.:

834

Cov.:

AF XY:

0.0316

AC XY:

22959

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00633

AC:

212

AN:

33480

American (AMR)

AF:

0.0113

AC:

505

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

345

AN:

26136

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0283

AC:

2445

AN:

86258

European-Finnish (FIN)

AF:

0.0172

AC:

920

AN:

53412

Middle Eastern (MID)

AF:

0.0432

AC:

249

AN:

5768

European-Non Finnish (NFE)

AF:

0.0355

AC:

39457

AN:

1111980

Other (OTH)

AF:

0.0327

AC:

1973

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

2809

5618

8427

11236

14045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1468

2936

4404

5872

7340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0226

AC:

3443

AN:

152290

Hom.:

Cov.:

AF XY:

0.0221

AC XY:

1642

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00782

AC:

325

AN:

41560

American (AMR)

AF:

0.0189

AC:

289

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0307

AC:

148

AN:

4826

European-Finnish (FIN)

AF:

0.0167

AC:

177

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0351

AC:

2386

AN:

68030

Other (OTH)

AF:

0.0204

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

186

373

559

746

932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0296

Hom.:

Bravo

AF:

0.0217

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.0

(source)

DANN

Benign

0.89

PhyloP100

-1.2

PromoterAI

0.013

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over