chr4-15567675-AG-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PP3_ModeratePP5_Very_Strong

The NM_001378615.1(CC2D2A):c.3289delG(p.Val1097fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000264 in 1,588,188 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 9.64

Publications

5 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: Pathogenic. The variant received 18 ACMG points.

PVS1

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

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 4-15567675-AG-A is Pathogenic according to our data. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567675-AG-A is described in CliVar as Pathogenic. Clinvar id is 56303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.3289delG	p.Val1097fs	frameshift_variant, splice_region_variant	Exon 26 of 37	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 link	c.3289delG	p.Val1097fs	frameshift_variant, splice_region_variant	Exon 27 of 38		NP_001073991.2	Q9P2K1-4
CC2D2A	NM_001378617.1 link	c.3142delG	p.Val1048fs	frameshift_variant, splice_region_variant	Exon 24 of 35		NP_001365546.1
LOC124900671	XR_007058061.1 link	n.130+3055delC		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.3289delG	p.Val1097fs	frameshift_variant, splice_region_variant	Exon 26 of 37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000216

AC:

AN:

222132

AF XY:

0.000191

show subpopulations

Gnomad AFR exome

AF:

0.0000683

Gnomad AMR exome

AF:

0.0000753

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000420

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000266

AC:

382

AN:

1435978

Hom.:

Cov.:

AF XY:

0.000266

AC XY:

190

AN XY:

713876

show subpopulations

African (AFR)

AF:

0.0000314

AC:

AN:

31854

American (AMR)

AF:

0.0000541

AC:

AN:

36980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25288

East Asian (EAS)

AF:

0.00

AC:

AN:

39454

South Asian (SAS)

AF:

0.00

AC:

AN:

80648

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

53136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.000326

AC:

360

AN:

1103466

Other (OTH)

AF:

0.000219

AC:

AN:

59428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000250

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.000291

Hom.:

Bravo

AF:

0.000283

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 27, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with COACH syndrome who harbored a second variant on the opposite allele and in two siblings with Joubert syndrome who did not have a second identifiable variant (Gorden et al., 2008; Bachmann-Gagescu et al., 2012); Reported in trans with another CC2D2A variant in a family with Meckel syndrome (Tallila et al., 2009); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18950740, 19466712, 19574260, 22241855, 26092869, 32488064, 33084218) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 18, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joubert syndrome 9

Pathogenic:5

Oct 27, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as compound heterozygous with NM_001080522.2:c.4786G>A. -

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 9, (MIM#612285); Meckel syndrome 6 (MIM#612284) and COACH syndrome (MIM#216360). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 54 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least 10 individuals, two of whom diagnosed with Joubert Syndrome (ClinVar; PMID: 28125082). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 17, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel syndrome, type 6

Pathogenic:2

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CC2D2A c.3289delG (p.Val1097PhefsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00022 in 222132 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CC2D2A causing Meckel Syndrome Type 6 (0.00022 vs 0.0011), allowing no conclusion about variant significance. c.3289delG has been reported in the literature in compound heterozygous individuals and heterozygous individuals with the second allele changes unidentified affected with Meckel Syndrome Type 6 (Tallila_2009, Gorden_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18950740, 19466712). ClinVar contains an entry for this variant (Variation ID: 56303). Based on the evidence outlined above, the variant was classified as pathogenic. -

Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93

Pathogenic:1

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

May 11, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3289delG (p.V1097Ffs*2) alteration, located in exon 27 (coding exon 25) of the CC2D2A gene, consists of a deletion of one nucleotide at position 3289, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been seen along with another CC2D2A alteration in multiple individuals with clinical features of CC2D2A-related ciliopathy (Doherty, 2010; Bachmann-Gagescu, 2012; Bachmann-Gagescu, 2015; Vilboux, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

See cases

Pathogenic:1

Dec 16, 2021

Institute of Human Genetics, University Hospital Muenster

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PVS1,PM2,PM3,PP5 -

COACH syndrome 2

Pathogenic:1

Jan 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Pathogenic:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Val1097Phefs*2) in the CC2D2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CC2D2A are known to be pathogenic (PMID: 19777577). This variant is present in population databases (rs770470219, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with Joubert syndrome and Meckel syndrome (PMID: 18950740, 19466712, 22241855). ClinVar contains an entry for this variant (Variation ID: 56303). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

CC2D2A-related disorder

Pathogenic:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CC2D2A c.3289delG variant is predicted to result in a frameshift and premature protein termination (p.Val1097Phefs*2). This variant has been reported in the compound heterozygous state in multiple individuals with Joubert syndrome and related disorders (see example: reported as p.V1097FfsX1 in Table 1, Gorden et al. 2008. PubMed ID: 18950740; Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CC2D2A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.6

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.82

Position offset: 3

DS_AL_spliceai

0.99

Position offset: 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