Variant rs797045437 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001378615.1(CC2D2A):c.4465_4468delGACA(p.Asp1489fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,553,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.44

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:

CC2D2A (HGNC:):

CC2D2A links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 4-15597431-TCAGA-T is Pathogenic according to our data. Variant chr4-15597431-TCAGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 linkuse as main transcript	c.4465_4468delGACA	p.Asp1489fs	frameshift_variant	35/37	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 linkuse as main transcript	c.4465_4468delGACA	p.Asp1489fs	frameshift_variant	36/38		NP_001073991.2	Q9P2K1-4
CC2D2A	NM_001378617.1 linkuse as main transcript	c.4318_4321delGACA	p.Asp1440fs	frameshift_variant	33/35		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.4465_4468delGACA	p.Asp1489fs	frameshift_variant	35/37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152176

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:

0.000961

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000618

AC:

AN:

161732

Hom.:

AF XY:

0.0000703

AC XY:

AN XY:

85312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.0000873

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000143

AC:

AN:

1400982

Hom.:

AF XY:

0.0000174

AC XY:

AN XY:

691222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000250

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000741

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000961

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	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: 26673778) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	May 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2017	- -

Joubert syndrome 9

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. NMD-predicted variants resulting in loss of protein function have previously been reported in this gene (ClinVar). (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 36 of 38). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple NMD-predicted variants have previously been reported pathogenic in clinical cases (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in clinical cases (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2023

This sequence change creates a premature translational stop signal (p.Asp1489Lysfs*15) 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 (rs797045437, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with nephronophthisis and Meckel-Gruber syndrome (PMID: 26673778). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 210612). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PVS1+PP4 -

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