7-116526606-G-A

Variant names:

• chr7-116526606-G-A
• rs121434501
• NM_001753.5:c.112G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001753.5(CAV1):​c.112G>A​(p.Glu38Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAV1 NM_001753.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.26
• Publications: 0 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
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.112G>A	p.Glu38Lys	missense	Exon 2 of 3	NP_001744.2
	CAV1	NM_001172895.1		c.19G>A	p.Glu7Lys	missense	Exon 2 of 3	NP_001166366.1	Q59E85
	CAV1	NM_001172896.2		c.19G>A	p.Glu7Lys	missense	Exon 1 of 2	NP_001166367.1	Q03135-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV1	ENST00000341049.7	TSL:1 MANE Select	c.112G>A	p.Glu38Lys	missense	Exon 2 of 3	ENSP00000339191.2	Q03135-1
	CAV1	ENST00000393467.1	TSL:1	c.19G>A	p.Glu7Lys	missense	Exon 1 of 2	ENSP00000377110.1	Q03135-2
	CAV1	ENST00000393468.1	TSL:1	c.19G>A	p.Glu7Lys	missense	Exon 2 of 3	ENSP00000377111.1	Q03135-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.58
Sift	Benign	0.053	T
Sift4G	Benign	0.47	T
Polyphen		0.38	B
Vest4		0.69
MutPred		0.47		Gain of ubiquitination at E38 (P = 0.0069)
MVP		0.99
MPC		1.4
ClinPred		0.98	D
GERP RS		5.4
PromoterAI		0.028	Neutral
Varity_R		0.21
gMVP		0.90
Mutation Taster		=53/47	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: rs121434501; hg19: chr7-116166660;