rs863225175

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_001378615.1(CC2D2A):c.4844_4847delCTCT(p.Ser1615LeufsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,543,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.28

Publications

2 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: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00391 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-15601403-CCTCT-C is Pathogenic according to our data. Variant chr4-15601403-CCTCT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217606.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CC2D2A	NM_001378615.1 link	c.4844_4847delCTCT	p.Ser1615LeufsTer16	frameshift_variant	Exon 37 of 37	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 link	c.4844_4847delCTCT	p.Ser1615LeufsTer16	frameshift_variant	Exon 38 of 38		NP_001073991.2
CC2D2A	NM_001378617.1 link	c.4697_4700delCTCT	p.Ser1566LeufsTer16	frameshift_variant	Exon 35 of 35		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.4844_4847delCTCT	p.Ser1615LeufsTer16	frameshift_variant	Exon 37 of 37	5	NM_001378615.1	ENSP00000403465.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000499

AC:

AN:

200572

AF XY:

0.00000922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

1391750

Hom.:

AF XY:

0.0000117

AC XY:

AN XY:

685066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31688

American (AMR)

AF:

0.00

AC:

AN:

36538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24072

East Asian (EAS)

AF:

0.00

AC:

AN:

38344

South Asian (SAS)

AF:

0.00

AC:

AN:

73932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5364

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

1073222

Other (OTH)

AF:

0.00

AC:

AN:

57414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 9

Pathogenic:1

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

CC2D2A-related disorder

Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CC2D2A c.4844_4847delCTCT variant is predicted to result in a frameshift disrupting the last 6 amino acids and extending the protein length by 9 amino acids (p.Ser1615Leufs*16). This variant has been reported in two patients with Joubert syndrome, in one along with a pathogenic missense variant and in the other with a splicing variant in CC2D2A (Bachmann-Gagescu et al. 2012. PubMed ID: 22241855). Additionally, here at PreventionGenetics, this variant was observed in trans with a pathogenic variant in a patient. This variant is reported in 0.0011% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CC2D2A are expected to be pathogenic. Given all the evidence, we interpret this variant as likely pathogenic. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Uncertain:1

Feb 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change results in a frameshift in the CC2D2A gene (p.Ser1615Leufs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the CC2D2A protein and extend the protein by 9 additional amino acid residues. This variant is present in population databases (rs776305976, gnomAD 0.002%). This frameshift has been observed in individual(s) with Joubert syndrome (PMID: 22241855). ClinVar contains an entry for this variant (Variation ID: 217606). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.3

Mutation Taster

=0/200

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over