rs1861050

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The ENST00000503658.2(CC2D2A):c.262C>T(p.Arg88*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0532 in 1,610,996 control chromosomes in the GnomAD database, including 4,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.079 ( 705 hom., cov: 32)

Exomes 𝑓: 0.051 ( 3535 hom. )

Consequence

CC2D2A
ENST00000503658.2 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -5.90

Publications

32 publications found

Variant links:

Genes affected

CC2D2A (HGNC:29253): (coiled-coil and C2 domain containing 2A) This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

CC2D2A Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
retinitis pigmentosa 93
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
COACH syndrome 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CC2D2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 4-15480736-C-T is Benign according to our data. Variant chr4-15480736-C-T is described in ClinVar as Benign. ClinVar VariationId is 126229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.156C>T	p.Ser52Ser	synonymous_variant	Exon 4 of 37	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.156C>T	p.Ser52Ser	synonymous_variant	Exon 4 of 37	5	NM_001378615.1	ENSP00000403465.1

Frequencies

GnomAD3 genomes

AF:

0.0788

AC:

11963

AN:

151892

Hom.:

709

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.186

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.159

Gnomad SAS

AF:

0.0772

Gnomad FIN

AF:

0.0657

Gnomad MID

AF:

0.0224

Gnomad NFE

AF:

0.0364

Gnomad OTH

AF:

0.0811

GnomAD2 exomes

AF:

0.0865

AC:

20893

AN:

241642

AF XY:

0.0774

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.00857

Gnomad EAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.0553

Gnomad NFE exome

AF:

0.0366

Gnomad OTH exome

AF:

0.0708

GnomAD4 exome

AF:

0.0505

AC:

73740

AN:

1458984

Hom.:

3535

Cov.:

AF XY:

0.0496

AC XY:

35990

AN XY:

725578

show subpopulations

African (AFR)

AF:

0.113

AC:

3772

AN:

33408

American (AMR)

AF:

0.256

AC:

11275

AN:

44084

Ashkenazi Jewish (ASJ)

AF:

0.00917

AC:

239

AN:

26058

East Asian (EAS)

AF:

0.164

AC:

6504

AN:

39540

South Asian (SAS)

AF:

0.0674

AC:

5773

AN:

85636

European-Finnish (FIN)

AF:

0.0557

AC:

2972

AN:

53310

Middle Eastern (MID)

AF:

0.0361

AC:

208

AN:

5762

European-Non Finnish (NFE)

AF:

0.0358

AC:

39724

AN:

1110872

Other (OTH)

AF:

0.0543

AC:

3273

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

3408

6815

10223

13630

17038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1732

3464

5196

6928

8660

<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:

0.0786

AC:

11954

AN:

152012

Hom.:

705

Cov.:

AF XY:

0.0828

AC XY:

6156

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.108

AC:

4495

AN:

41430

American (AMR)

AF:

0.186

AC:

2838

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3470

East Asian (EAS)

AF:

0.158

AC:

814

AN:

5144

South Asian (SAS)

AF:

0.0763

AC:

367

AN:

4812

European-Finnish (FIN)

AF:

0.0657

AC:

695

AN:

10586

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0364

AC:

2473

AN:

67990

Other (OTH)

AF:

0.0817

AC:

172

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

543

1087

1630

2174

2717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0520

Hom.:

1342

Bravo

AF:

0.0904

TwinsUK

AF:

0.0369

AC:

137

ALSPAC

AF:

0.0355

AC:

137

ESP6500AA

AF:

0.0980

AC:

371

ESP6500EA

AF:

0.0376

AC:

310

ExAC

AF:

0.0781

AC:

9436

Asia WGS

AF:

0.124

AC:

432

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Oct 09, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23352160, 27535653) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Joubert syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel syndrome, type 6

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 9

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.16

(source)

DANN

Benign

0.80

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0011

PhyloP100

-5.9

Vest4

0.43

GERP RS

-9.3

Mutation Taster

=188/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over