4-15586170-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001378615.1(CC2D2A):​c.3989G>A​(p.Arg1330Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,609,868 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. R1330L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

2
12
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 3.46

Publications

2 publications found
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 Gene-Disease associations (from GenCC):
  • ciliopathy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • Joubert syndrome 9
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
  • retinitis pigmentosa 93
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • COACH syndrome 1
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Joubert syndrome with oculorenal defect
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Meckel syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.869
PP5
Variant 4-15586170-G-A is Pathogenic according to our data. Variant chr4-15586170-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217612.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CC2D2ANM_001378615.1 linkc.3989G>A p.Arg1330Gln missense_variant Exon 31 of 37 ENST00000424120.6 NP_001365544.1
CC2D2ANM_001080522.2 linkc.3989G>A p.Arg1330Gln missense_variant Exon 32 of 38 NP_001073991.2 Q9P2K1-4
CC2D2ANM_001378617.1 linkc.3842G>A p.Arg1281Gln missense_variant Exon 29 of 35 NP_001365546.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CC2D2AENST00000424120.6 linkc.3989G>A p.Arg1330Gln missense_variant Exon 31 of 37 5 NM_001378615.1 ENSP00000403465.1 Q9P2K1-4

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152138
Hom.:
0
Cov.:
32
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000202
AC:
5
AN:
247880
AF XY:
0.0000372
show subpopulations
Gnomad AFR exome
AF:
0.0000649
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1457730
Hom.:
0
Cov.:
29
AF XY:
0.0000221
AC XY:
16
AN XY:
725276
show subpopulations
African (AFR)
AF:
0.0000599
AC:
2
AN:
33388
American (AMR)
AF:
0.00
AC:
0
AN:
44450
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26046
East Asian (EAS)
AF:
0.0000253
AC:
1
AN:
39560
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53312
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5754
European-Non Finnish (NFE)
AF:
0.0000198
AC:
22
AN:
1109230
Other (OTH)
AF:
0.00
AC:
0
AN:
60160
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.446
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152138
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74328
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41412
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10602
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93 Pathogenic:1
Jun 19, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Pathogenic:1
Feb 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1330 of the CC2D2A protein (p.Arg1330Gln). This variant is present in population databases (rs763486732, gnomAD 0.004%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217612). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CC2D2A protein function. For these reasons, this variant has been classified as Pathogenic. -

Joubert syndrome 9 Pathogenic:1
Feb 23, 2015
UW Hindbrain Malformation Research Program, University of Washington
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

not specified Uncertain:1
Jul 12, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: CC2D2A c.3989G>A (p.Arg1330Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247880 control chromosomes (gnomAD). c.3989G>A has been reported in the literature in individuals affected with Joubert syndrome (example: Bachmann-Gagescu_2015). These data indicate that the variant may 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: 22241855, 30055837, 33502066). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and VUS (n=1)Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1
Apr 21, 2023
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.063
T
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.60
D;D
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.95
D;.
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Benign
-0.41
T
MutationAssessor
Uncertain
2.7
M;M
PhyloP100
3.5
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-3.2
D;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.0060
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
1.0
D;D
Vest4
0.83
MVP
0.80
MPC
0.28
ClinPred
0.92
D
GERP RS
3.4
Varity_R
0.31
gMVP
0.80
Mutation Taster
=23/77
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs763486732; hg19: chr4-15587793; COSMIC: COSV101052789; COSMIC: COSV101052789; API