Variant rs896947430 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001378615.1(CC2D2A):c.100C>T(p.Arg34*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,554,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: -0.160

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-15478783-C-T is Pathogenic according to our data. Variant chr4-15478783-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377067.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.100C>T	p.Arg34*	stop_gained	3/37	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.100C>T	p.Arg34*	stop_gained	3/37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000617

AC:

AN:

161988

Hom.:

AF XY:

0.0000117

AC XY:

AN XY:

85108

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000220

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1401888

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

691664

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000204

Gnomad4 OTH exome

AF:

0.0000343

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 14, 2016	- -
Pathogenic, criteria provided, single submitter	research	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -

CC2D2A-related disorder

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	research	MUHC Nephrogenetics Laboratory, Research Institute of the McGill University Health Centre	Jun 14, 2024	Genetic testing identified a homozygous nonsense variant in the gene CC2D2A: NM_001378615.1(CC2D2A):c.100C>T (p.Arg34Ter). The variant was classified as a variant of uncertain significance (VUS) by the clinical laboratory. It is extremely rare in the reference population and generates a premature stop codon in exon 3 of the canonical transcript (NM_001378615.1). Using in silico prediction tools, p.(Arg34) is not expected to efficiently trigger NMD, nor completely escape NMD, suggesting a potential partial loss-of-function effect. Both predictive and in vitro models of the CC2D2A p.(Arg34) nonsense variant suggest translation re-initiation may occur at the downstream translation initiation site, potentially recovering residual protein function. The region that is lost from the full-length CC2D2A protein isoform (amino acid residues 1-49) does not contain any annotated functional protein domains, nor does it contain any reported interaction sites or localization signals, suggesting the shorter protein may retain function. Transcript-isoform expression analysis revealed that this variant primarily affects kidney-predominant transcripts. We conclude that the reduction of the kidney enriched CC2D2A protein isoform may result in progressive and degenerative renal disease. ACMG Classification: The CC2D2A c.100C>T, p.(Arg34*) was classified as a variant of uncertain significance (VUS) because insufficient evidence existed to support its pathogenicity. Variant interpretation was performed based on the general recommendations from the Sequence Variant Interpretation (SVI) Working Group for using ACMG/AMP Criteria (Clinical Genome Resource). Population Data: The variant is extremely rare in a healthy population database (gnomAD v2.1.1); however, the patient has Cree ancestry, which is not represented in population databases; therefore, the variant frequency in Cree population is not known. Therefore, PM2 cannot be invoked. Computational & Predictive Data: Nonsense variant in the gene CC2D2A, predicted to cause NMD. Loss-of-function is a known mechanism of disease. Exons 1-3 are biologically relevant to kidney function. SVI Working Group reached a consensus agreement that removing >10% of the protein product is more likely to have a loss of function effect compared to variants that remove <10%. PVS1_Strong was therefore invoked according to the recommended guidelines. Other Databases: The variant has been reported on ClinVar as Pathogenic and Likely Pathogenic, but without phenotype information. PP5 was not invoked according to recommended guidelines. -
Likely pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 12, 2024	The CC2D2A c.100C>T variant is predicted to result in premature protein termination (p.Arg34*). To our knowledge, this variant has not been reported in individuals with CC2D2A-associated disorders in the literature or in a large population database, indicating this variant is rare. Nonsense variants in CC2D2A are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change creates a premature translational stop signal (p.Arg34*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 377067). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.011

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.14

Vest4

0.57

GERP RS

1.3

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over