4-15480698-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378615.1(CC2D2A):c.124-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0713 in 1,606,312 control chromosomes in the GnomAD database, including 11,290 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 4244 hom., cov: 31)

Exomes 𝑓: 0.061 ( 7046 hom. )

Consequence

CC2D2A
NM_001378615.1 splice_region, intron

Scores

Splicing: ADA: 0.00002531

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.06

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 4-15480698-C-T is Benign according to our data. Variant chr4-15480698-C-T is described in ClinVar as Benign. ClinVar VariationId is 93531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.124-6C>T		splice_region_variant, intron_variant	Intron 3 of 36	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.124-6C>T		splice_region_variant, intron_variant	Intron 3 of 36	5	NM_001378615.1	ENSP00000403465.1

Frequencies

GnomAD3 genomes

AF:

0.167

AC:

25398

AN:

151832

Hom.:

4238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.415

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.158

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.0654

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0375

Gnomad OTH

AF:

0.144

GnomAD2 exomes

AF:

0.110

AC:

26052

AN:

236020

AF XY:

0.0975

show subpopulations

Gnomad AFR exome

AF:

0.422

Gnomad AMR exome

AF:

0.273

Gnomad ASJ exome

AF:

0.00858

Gnomad EAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.0545

Gnomad NFE exome

AF:

0.0367

Gnomad OTH exome

AF:

0.0815

GnomAD4 exome

AF:

0.0612

AC:

89070

AN:

1454362

Hom.:

7046

Cov.:

AF XY:

0.0600

AC XY:

43400

AN XY:

722902

show subpopulations

African (AFR)

AF:

0.436

AC:

14493

AN:

33260

American (AMR)

AF:

0.269

AC:

11622

AN:

43196

Ashkenazi Jewish (ASJ)

AF:

0.00933

AC:

242

AN:

25934

East Asian (EAS)

AF:

0.164

AC:

6464

AN:

39340

South Asian (SAS)

AF:

0.0976

AC:

8281

AN:

84806

European-Finnish (FIN)

AF:

0.0553

AC:

2934

AN:

53024

Middle Eastern (MID)

AF:

0.0578

AC:

332

AN:

5748

European-Non Finnish (NFE)

AF:

0.0361

AC:

40062

AN:

1108908

Other (OTH)

AF:

0.0771

AC:

4640

AN:

60146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

3556

7112

10667

14223

17779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1902

3804

5706

7608

9510

<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:

0.167

AC:

25427

AN:

151950

Hom.:

4244

Cov.:

AF XY:

0.169

AC XY:

12539

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.415

AC:

17155

AN:

41340

American (AMR)

AF:

0.215

AC:

3282

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3468

East Asian (EAS)

AF:

0.158

AC:

812

AN:

5144

South Asian (SAS)

AF:

0.108

AC:

520

AN:

4810

European-Finnish (FIN)

AF:

0.0654

AC:

694

AN:

10608

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0376

AC:

2554

AN:

68002

Other (OTH)

AF:

0.144

AC:

303

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

834

1669

2503

3338

4172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.0790

Hom.:

2130

Bravo

AF:

0.190

Asia WGS

AF:

0.164

AC:

571

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

- -

Sep 17, 2013

Eurofins Ntd Llc (ga)

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. -

Oct 09, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel syndrome, type 6

Benign:1

Jan 13, 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 13, 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_noAF

Benign

-0.85

CADD

Benign

7.5

(source)

DANN

Benign

0.31

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000025

dbscSNV1_RF

Benign

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over