rs863225175

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4PP5

The NM_001378615.1(CC2D2A):c.4844_4847del(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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1699 codons.

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 id is 217606.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr4-15601403-CCTCT-C is described in Lovd as [Pathogenic]. Variant chr4-15601403-CCTCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CC2D2A	NM_001378615.1 linkuse as main transcript	c.4844_4847del	p.Ser1615LeufsTer16	frameshift_variant	37/37	ENST00000424120.6
CC2D2A	NM_001080522.2 linkuse as main transcript	c.4844_4847del	p.Ser1615LeufsTer16	frameshift_variant	38/38
CC2D2A	NM_001378617.1 linkuse as main transcript	c.4697_4700del	p.Ser1566LeufsTer16	frameshift_variant	35/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.4844_4847del	p.Ser1615LeufsTer16	frameshift_variant	37/37	5	NM_001378615.1	P1	Q9P2K1-4

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

GnomAD3 exomes

AF:

0.00000499

AC:

AN:

200572

Hom.:

AF XY:

0.00000922

AC XY:

AN XY:

108472

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:

0.0000109

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

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:

0.0000130

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

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

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2021

- -

CC2D2A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2023

The CC2D2A c.4844_4847delCTCT variant is predicted to result in a frameshift and premature protein termination (p.Ser1615Leufs*16). This variant has been reported along with a splicing variant in CC2D2A in an individual with Joubert syndrome (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 (http://gnomad.broadinstitute.org/variant/4-15603026-CCTCT-C). Frameshift variants in CC2D2A are expected to be pathogenic. Given all the evidence, we interpret this variant as likely pathogenic. -

Joubert syndrome 9

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2022

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

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