rs188891842
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001378615.1(CC2D2A):c.3577A>G(p.Ile1193Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000942 in 1,602,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000050 ( 0 hom. )
Consequence
CC2D2A
NM_001378615.1 missense
NM_001378615.1 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 3.85
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_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.017707825).
BP6
?
Variant 4-15570479-A-G is Benign according to our data. Variant chr4-15570479-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288557.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CC2D2A | NM_001378615.1 | c.3577A>G | p.Ile1193Val | missense_variant | 28/37 | ENST00000424120.6 | |
LOC124900671 | XR_007058061.1 | n.130+252T>C | intron_variant, non_coding_transcript_variant | ||||
CC2D2A | NM_001080522.2 | c.3577A>G | p.Ile1193Val | missense_variant | 29/38 | ||
CC2D2A | NM_001378617.1 | c.3430A>G | p.Ile1144Val | missense_variant | 26/35 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CC2D2A | ENST00000424120.6 | c.3577A>G | p.Ile1193Val | missense_variant | 28/37 | 5 | NM_001378615.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000506 AC: 77AN: 152210Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000156 AC: 37AN: 237746Hom.: 0 AF XY: 0.0000857 AC XY: 11AN XY: 128360
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GnomAD4 exome AF: 0.0000496 AC: 72AN: 1450194Hom.: 0 Cov.: 27 AF XY: 0.0000388 AC XY: 28AN XY: 720850
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GnomAD4 genome ? AF: 0.000519 AC: 79AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41AN XY: 74494
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
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) | Aug 17, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28518168) - |
Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5435651:COACH syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | - - |
CC2D2A-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at