Variant 4-15559183-C-T 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.2848C>T(p.Arg950Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000226 in 1,549,740 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.88

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 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 4-15559183-C-T is Pathogenic according to our data. Variant chr4-15559183-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15559183-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1 linkuse as main transcript	c.2848C>T	p.Arg950Ter	stop_gained	22/37	ENST00000424120.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.2848C>T	p.Arg950Ter	stop_gained	22/37	5	NM_001378615.1	P1	Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000623

AC:

AN:

160490

Hom.:

AF XY:

0.0000119

AC XY:

AN XY:

83954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000413

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:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1397668

Hom.:

Cov.:

AF XY:

0.0000247

AC XY:

AN XY:

689442

show subpopulations

Gnomad4 AFR exome

AF:

0.0000954

Gnomad4 AMR exome

AF:

0.0000283

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000767

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000176

Gnomad4 OTH exome

AF:

0.0000516

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000278

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000187

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2023	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26092869, 27959436, 31618753, 18950740) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 22, 2023	PM2, PS4_moderate, PVS1 -

Joubert syndrome 9

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 745). This premature translational stop signal has been observed in individuals with clinical features of Joubert syndrome (PMID: 18950740, 27959436, 31618753). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg950*) 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). -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2017

- -

CC2D2A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2023

The CC2D2A c.2848C>T variant is predicted to result in premature protein termination (p.Arg950*). This variant has been reported in individuals with Joubert syndrome (Gorden et al 2008. PubMed ID: 18950740; Xiao D et al 2016. PubMed ID: 27959436; Table S1, Ziats MN et al 2019. PubMed ID: 31618753). This variant is reported in 0.0041% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-15560806-C-T). Nonsense 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

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.87

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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