chr4-15599615-G-A

Position:

chr4-15599615-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_001378615.1(CC2D2A):c.4583G>A(p.Arg1528His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,232 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1528C) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 7.51

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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-15599614-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CC2D2A	NM_001378615.1 linkuse as main transcript	c.4583G>A	p.Arg1528His	missense_variant	36/37	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 linkuse as main transcript	c.4583G>A	p.Arg1528His	missense_variant	37/38		NP_001073991.2
CC2D2A	NM_001378617.1 linkuse as main transcript	c.4436G>A	p.Arg1479His	missense_variant	34/35		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.4583G>A	p.Arg1528His	missense_variant	36/37	5	NM_001378615.1	ENSP00000403465	P1	Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248706

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134932

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461094

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726842

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2023	Reported with another CC2D2A variant in a proband with a Joubert syndrome related disorder, but detailed clinical information was not provided and it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Ben-Salem et al., 2014); Reported as a single heterozygous variant in a proband with polydactyly (Zu et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27082236, 34194672, 27081510, 31577543, 33486889) -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 11, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1528 of the CC2D2A protein (p.Arg1528His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 27081510, 31964843, 34194672). ClinVar contains an entry for this variant (Variation ID: 597406). 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 80%. This variant disrupts the p.Arg1528 amino acid residue in CC2D2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18950740). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

COACH syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PM1,PM5,PM3,PM2,PP3 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 17, 2023

Variant summary: CC2D2A c.4583G>A (p.Arg1528His) 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 4e-06 in 248706 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4583G>A has been reported in the literature in at least one individual affected with a Joubert syndrome-related disorder (e.g., Ben-Salem_2014, Ben-Salem_2015) as well as an individual with polydactyly (e.g., Zu_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) have cited the variant: one submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. In addition, p.R1528C has been reported as pathogenic in ClinVar and to associate with Joubert syndrome (HGMD database). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CC2D2A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2023

The CC2D2A c.4583G>A variant is predicted to result in the amino acid substitution p.Arg1528His. This variant was previously reported, in the compound heterozygous state with a protein-truncating variant, in an individual who presented with Joubert syndrome (Ben-Salem et al. 2014. PubMed ID: 27081510); a different amino acid substitution at this position (p.Arg1528Cys) was also reported in the same study in two affected individuals. This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-15601238-G-A). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

D;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;.

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.58

MutPred

0.54

Loss of MoRF binding (P = 0.0183);Loss of MoRF binding (P = 0.0183);

MVP

0.92

MPC

0.14

ClinPred

0.97

GERP RS

5.8

Varity_R

0.39

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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