NM_001378615.1:c.3183-8T>C

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.3183-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,600,468 control chromosomes in the GnomAD database, including 404,297 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 0.69 ( 36510 hom., cov: 31)

Exomes 𝑓: 0.71 ( 367787 hom. )

Consequence

CC2D2A
NM_001378615.1 splice_region, intron

Scores

Splicing: ADA: 0.00001021

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0100

Publications

18 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:

LOC124900671 (HGNC:):

LOC124900671 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=-0.89).

BP6

Variant 4-15567369-T-C is Benign according to our data. Variant chr4-15567369-T-C is described in ClinVar as Benign. ClinVar VariationId is 126236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.3183-8T>C	splice_region_variant, intron_variant	Intron 24 of 36	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 link	c.3183-8T>C	splice_region_variant, intron_variant	Intron 25 of 37		NP_001073991.2	Q9P2K1-4
CC2D2A	NM_001378617.1 link	c.3036-8T>C	splice_region_variant, intron_variant	Intron 22 of 34		NP_001365546.1
LOC124900671	XR_007058061.1 link	n.131-3173A>G	intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.3183-8T>C		splice_region_variant, intron_variant	Intron 24 of 36	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.691

AC:

104976

AN:

151848

Hom.:

36483

Cov.:

show subpopulations

Gnomad AFR

AF:

0.631

Gnomad AMI

AF:

0.867

Gnomad AMR

AF:

0.759

Gnomad ASJ

AF:

0.736

Gnomad EAS

AF:

0.540

Gnomad SAS

AF:

0.708

Gnomad FIN

AF:

0.678

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.721

Gnomad OTH

AF:

0.686

GnomAD2 exomes

AF:

0.709

AC:

173646

AN:

244966

AF XY:

0.708

show subpopulations

Gnomad AFR exome

AF:

0.635

Gnomad AMR exome

AF:

0.792

Gnomad ASJ exome

AF:

0.722

Gnomad EAS exome

AF:

0.527

Gnomad FIN exome

AF:

0.685

Gnomad NFE exome

AF:

0.723

Gnomad OTH exome

AF:

0.724

GnomAD4 exome

AF:

0.712

AC:

1030645

AN:

1448502

Hom.:

367787

Cov.:

AF XY:

0.712

AC XY:

513631

AN XY:

721408

show subpopulations

African (AFR)

AF:

0.631

AC:

20895

AN:

33126

American (AMR)

AF:

0.788

AC:

34516

AN:

43800

Ashkenazi Jewish (ASJ)

AF:

0.724

AC:

18796

AN:

25964

East Asian (EAS)

AF:

0.562

AC:

22236

AN:

39542

South Asian (SAS)

AF:

0.714

AC:

60908

AN:

85266

European-Finnish (FIN)

AF:

0.684

AC:

36466

AN:

53342

Middle Eastern (MID)

AF:

0.718

AC:

4105

AN:

5720

European-Non Finnish (NFE)

AF:

0.718

AC:

790868

AN:

1101822

Other (OTH)

AF:

0.699

AC:

41855

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

14650

29299

43949

58598

73248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19664

39328

58992

78656

98320

<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:

0.691

AC:

105044

AN:

151966

Hom.:

36510

Cov.:

AF XY:

0.689

AC XY:

51218

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.632

AC:

26195

AN:

41450

American (AMR)

AF:

0.758

AC:

11582

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.736

AC:

2555

AN:

3470

East Asian (EAS)

AF:

0.540

AC:

2785

AN:

5156

South Asian (SAS)

AF:

0.707

AC:

3406

AN:

4820

European-Finnish (FIN)

AF:

0.678

AC:

7147

AN:

10548

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.721

AC:

48949

AN:

67934

Other (OTH)

AF:

0.681

AC:

1435

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1654

3308

4962

6616

8270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

822

1644

2466

3288

4110

<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:

0.713

Hom.:

30160

Bravo

AF:

0.696

Asia WGS

AF:

0.643

AC:

2234

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 24, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Meckel syndrome, type 6

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Joubert syndrome 9

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.89

CADD

Benign

6.0

(source)

DANN

Benign

0.50

PhyloP100

-0.010

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000010

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