Variant rs386833757 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.3774dup(p.Glu1259Ter) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,611,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.73

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 4-15579967-G-GT is Pathogenic according to our data. Variant chr4-15579967-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 56309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	MANE	Protein
CC2D2A	NM_001378615.1 linkuse as main transcript	c.3774dup	p.Glu1259Ter	frameshift_variant, splice_region_variant	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 linkuse as main transcript	c.3774dup	p.Glu1259Ter	frameshift_variant, splice_region_variant		NP_001073991.2
CC2D2A	NM_001378617.1 linkuse as main transcript	c.3627dup	p.Glu1210Ter	frameshift_variant, splice_region_variant		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.3774dup	p.Glu1259Ter	frameshift_variant, splice_region_variant		5	NM_001378615.1	ENSP00000403465	P1	Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000523

AC:

AN:

248792

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134978

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:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000216

AC:

315

AN:

1459422

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

726112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.000274

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000965

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.0000604

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2022	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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24706459, 26729329, 21866095, 26092869, 21068128, 33486889) -

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.Glu1259*) 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 (rs757195653, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with CC2D2A-related conditions (PMID: 21068128, 26092869). ClinVar contains an entry for this variant (Variation ID: 56309). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

COACH syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics England Pilot Project, Genomics England

- -

Ciliopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Mar 01, 2024

This sequence change in CC2D2A is a frameshift variant predicted to cause a premature stop codon, p.(Glu1259*), in biologically relevant exon 30/37 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.03% (314/1,178,816 alleles) in the European (non-Finnish) population, consistent with a recessive disease. This variant has been detected in at least five individuals with a phenotype consistent with a ciliopathy (Meckel syndrome and Joubert syndrome) in the compound heterozygous state (with at least one individual with a pathogenic variant on the other allele; PMID: 21068128, 24706459, 26092869, 26729329). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting. -

Meckel syndrome, type 6

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

- -

Joubert syndrome 9

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

CC2D2A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2024

The CC2D2A c.3774dupT variant is predicted to result in premature protein termination (p.Glu1259*). This variant has been reported in individuals with Meckel-Gruber syndrome (Otto et al. 2011. PubMed ID: 21068128; Jones et al. 2014. PubMed ID: 24706459). This variant is reported in 0.012% of alleles in individuals of European (non-Finnish) descent in gnomAD. Truncating 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

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: 0

DS_AL_spliceai

0.47

Position offset: 1

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