rs118204052

Positions:

chr4-15599614-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001378615.1(CC2D2A):c.4582C>T(p.Arg1528Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,612,876 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1528H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.64

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-15599614-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2948795.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

PP5

Variant 4-15599614-C-T is Pathogenic according to our data. Variant chr4-15599614-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15599614-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CC2D2A	NM_001378615.1 linkuse as main transcript	c.4582C>T	p.Arg1528Cys	missense_variant	36/37	ENST00000424120.6
CC2D2A	NM_001080522.2 linkuse as main transcript	c.4582C>T	p.Arg1528Cys	missense_variant	37/38
CC2D2A	NM_001378617.1 linkuse as main transcript	c.4435C>T	p.Arg1479Cys	missense_variant	34/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.4582C>T	p.Arg1528Cys	missense_variant	36/37	5	NM_001378615.1	P1	Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248638

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1460766

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726654

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74290

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000547

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2018	A likely pathogenic variant has been identified in the CC2D2A gene. The R1528C variant has been reported previously in trans with the c.3774dupT variant in an individual with JSRD (Bachmann-Gagescu et al., 2015). Additionally, R1528C has been observed in trans with other CC2D2A variants (c.3289delG; c.3772-1G>T) and in the homozygous state in association with COACH syndrome and JSRD (Bachmann-Gagescu et al., 2015; Gorden et al., 2008). Different missense variants at the same codon (R1528H) and in a nearby residue (T1526N) have also been reported in the Human Gene Mutation Database in association with Joubert syndrome (Ben-Salem et al., 2014; Stenson et al., 2014). The R1528C variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species; however, the R1528C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the R1528C variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 14, 2022	- -

Joubert syndrome 9

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1528 of the CC2D2A protein (p.Arg1528Cys). This variant is present in population databases (rs118204052, gnomAD 0.003%). This missense change has been observed in individual(s) with CC2D2A-related conditions (PMID: 18950740). ClinVar contains an entry for this variant (Variation ID: 744). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CC2D2A protein function with a positive predictive value of 95%. 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 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

Meckel syndrome, type 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 15, 2023

Variant summary: CC2D2A c.4582C>T (p.Arg1528Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248638 control chromosomes. c.4582C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with features of Ciliopathies such as Joubert Syndrome/Meckel Syndrome (example, Bachmann-Gagescu_2015, Gorden_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26092869, 18950740). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

CC2D2A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2023

The CC2D2A c.4582C>T variant is predicted to result in the amino acid substitution p.Arg1528Cys. This variant has been reported in the compound heterozygous state in at least two unrelated individuals with Joubert syndrome (Gorden et al 2008. PubMed ID: 18950740; Bachmann-Gagescu R et al 2015. PubMed ID: 26092869). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-15601237-C-T). Different missense variants affecting the same amino acid (p. Arg1528His and p. Arg1528Cys) have been reported as causative for Joubert syndrome or related disorders (Ben-Salem. 2014. PubMed ID: 27081510; Gorden. 2008. PubMed ID: 18950740). Taken together, the c.4582C>T (p.Arg1528Cys) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;.

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.72

MutPred

0.55

Loss of MoRF binding (P = 0.0062);Loss of MoRF binding (P = 0.0062);

MVP

0.93

MPC

0.33

ClinPred

0.99

GERP RS

5.8

Varity_R

0.55

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.46

Position offset: 22

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