9-100586047-AGAGAGAGGCTAAGGCAGTCAG-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM4PP3BP6_Very_StrongBS2

The NM_001018116.2(CAVIN4):c.702_722delAAGGCAGTCAGGAGAGAGGCT(p.Arg235_Leu241del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,614,020 control chromosomes in the GnomAD database, including 11 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 10 hom. )

Consequence

CAVIN4
NM_001018116.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 9.26

Publications

0 publications found

Variant links:

Genes affected

CAVIN4 (HGNC:33742): (caveolae associated protein 4) This gene encodes a protein containing two coiled-coil regions. The encoded protein promotes Rho/ROCK (Rho-kinase) signaling in cardiac muscles cells, and may facilitate myofibrillar organization. [provided by RefSeq, Jun 2013]

CAVIN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001018116.2.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 9-100586047-AGAGAGAGGCTAAGGCAGTCAG-A is Benign according to our data. Variant chr9-100586047-AGAGAGAGGCTAAGGCAGTCAG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 227559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAVIN4	NM_001018116.2 link	c.702_722delAAGGCAGTCAGGAGAGAGGCT	p.Arg235_Leu241del	disruptive_inframe_deletion	Exon 2 of 2	ENST00000307584.6	NP_001018126.1	Q5BKX8
CAVIN4	XM_047423346.1 link	c.678_698delAAGGCAGTCAGGAGAGAGGCT	p.Arg227_Leu233del	disruptive_inframe_deletion	Exon 3 of 3		XP_047279302.1
CAVIN4	XM_047423347.1 link	c.315_335delAAGGCAGTCAGGAGAGAGGCT	p.Arg106_Leu112del	disruptive_inframe_deletion	Exon 2 of 2		XP_047279303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAVIN4	ENST00000307584.6 link	c.702_722delAAGGCAGTCAGGAGAGAGGCT	p.Arg235_Leu241del	disruptive_inframe_deletion	Exon 2 of 2	1	NM_001018116.2	ENSP00000418668.1		Q5BKX8

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

334

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00407

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00263

AC:

660

AN:

251226

AF XY:

0.00264

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00486

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00344

AC:

5025

AN:

1461694

Hom.:

AF XY:

0.00333

AC XY:

2423

AN XY:

727154

show subpopulations

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

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.000716

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000916

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00204

AC:

109

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00409

AC:

4543

AN:

1111836

Other (OTH)

AF:

0.00396

AC:

239

AN:

60384

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.374

Heterozygous variant carriers

231

462

692

923

1154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.00219

AC:

334

AN:

152326

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

41578

American (AMR)

AF:

0.000850

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00407

AC:

277

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00237

Hom.:

EpiCase

AF:

0.00338

EpiControl

AF:

0.00338

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CAVIN4: BS2 -

May 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21642240) -

not specified

Benign:1

Mar 21, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Leu248_Arg254del in exon 2 of MURC: This variant falls within a 7 amino acid r epeat (LRQSGER) and results in the removal of one repeat unit as compared to the reference sequence. Although it has been reported in three individuals with car diomyopathy (Rodriguez 2011), it is not expected to have clinical significance b ecause it has also been identified in 0.6% (369/66702) of European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Moreo ver, this region lacks conservation across species, and >5 mammals show a loss o f a single repeat unit within this region. -

CAVIN4-related disorder

Benign:1

Jan 06, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.3

Mutation Taster

=148/52

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over