chr4-15596207-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001378615.1(CC2D2A):c.4437G>A(p.Gln1479=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000737 in 1,357,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.4e-7 ( 0 hom. )
Consequence
CC2D2A
NM_001378615.1 splice_region, synonymous
NM_001378615.1 splice_region, synonymous
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.38
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CC2D2A | NM_001378615.1 | c.4437G>A | p.Gln1479= | splice_region_variant, synonymous_variant | 34/37 | ENST00000424120.6 | |
CC2D2A | NM_001080522.2 | c.4437G>A | p.Gln1479= | splice_region_variant, synonymous_variant | 35/38 | ||
CC2D2A | NM_001378617.1 | c.4290G>A | p.Gln1430= | splice_region_variant, synonymous_variant | 32/35 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CC2D2A | ENST00000424120.6 | c.4437G>A | p.Gln1479= | splice_region_variant, synonymous_variant | 34/37 | 5 | NM_001378615.1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 7.37e-7 AC: 1AN: 1357608Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 668050
GnomAD4 exome
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1
AN:
1357608
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29
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0
AN XY:
668050
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change affects codon 1479 of the CC2D2A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CC2D2A protein. This variant also falls at the last nucleotide of exon 35, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1023694). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at