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
Consequence
NM_001378615.1 missense
Scores
Clinical Significance
Conservation
Publications
- ciliopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Joubert syndrome 9Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
- retinitis pigmentosa 93Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- COACH syndrome 1Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Joubert syndrome with oculorenal defectInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Meckel syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CC2D2A | NM_001378615.1 | c.3989G>A | p.Arg1330Gln | missense_variant | Exon 31 of 37 | ENST00000424120.6 | NP_001365544.1 | |
CC2D2A | NM_001080522.2 | c.3989G>A | p.Arg1330Gln | missense_variant | Exon 32 of 38 | NP_001073991.2 | ||
CC2D2A | NM_001378617.1 | c.3842G>A | p.Arg1281Gln | missense_variant | Exon 29 of 35 | NP_001365546.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152138Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000202 AC: 5AN: 247880 AF XY: 0.0000372 show subpopulations
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1457730Hom.: 0 Cov.: 29 AF XY: 0.0000221 AC XY: 16AN XY: 725276 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93 Pathogenic:1
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Meckel-Gruber syndrome;C0431399:Joubert syndrome Pathogenic:1
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
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not specified Uncertain:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at