chr7-116525092-G-C

Variant names:

• chr7-116525092-G-C
• NM_001753.5:c.30G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001753.5(CAV1):​c.30G>C​(p.Glu10Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAV1 NM_001753.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAV1	NM_001753.5	c.30G>C	p.Glu10Asp	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000341049.7	NP_001744.2
CAV1	NM_001172895.1	c.-777G>C		5_prime_UTR_variant	Exon 1 of 3		NP_001166366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAV1	ENST00000341049.7	c.30G>C	p.Glu10Asp	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_001753.5	ENSP00000339191.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary hypertension, primary, 3 Uncertain:1

Jul 17, 2020

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous c.30G>C (p.Glu10Asp) variant identified in the CAV1 gene substitutes a Glutamic Acid for Aspartic Acid at amino acid 10/179 (exon 1/3). The p.Glu10 residue is the last amino acid in exon 1, and he c.30G is the last nucleotide in exon 1, and in addition to the missense change at the protein level, this nucleotidemay also be involved in splicing. Both the Glutamic Acid at this position as well as the Guanine nucleotide at this position are well conserved. This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms do not agree on the effect of this missense variant, as it is predicted both Neutral (Provean; score:-0.29) and Damaging (SIFT; score:0.049) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. The p.Glu10 residue is within a region of CAV1 that is required for homooligomerization (UniProtKB:Q03135). Given the lack of compelling evidence for its pathogenicity, the c.30G>C (p.Glu10Asp) variant identified in the CAV1 gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.29	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.049	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.0010	B;.
Vest4		0.27
MutPred		0.54		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP		0.99
MPC		0.54
ClinPred		0.84	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116165146;