rs117667651
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001378615.1(CC2D2A):c.4438-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,546,552 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00051 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00051 ( 2 hom. )
Consequence
CC2D2A
NM_001378615.1 intron
NM_001378615.1 intron
Scores
2
Splicing: ADA: 0.005747
2
Clinical Significance
Conservation
PhyloP100: 1.02
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 Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 4-15597398-C-A is Benign according to our data. Variant chr4-15597398-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238279.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}. Variant chr4-15597398-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000506 (706/1394330) while in subpopulation EAS AF= 0.0128 (458/35760). AF 95% confidence interval is 0.0118. There are 2 homozygotes in gnomad4_exome. There are 366 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CC2D2A | NM_001378615.1 | c.4438-9C>A | intron_variant | ENST00000424120.6 | NP_001365544.1 | |||
| CC2D2A | NM_001080522.2 | c.4438-9C>A | intron_variant | NP_001073991.2 | ||||
| CC2D2A | NM_001378617.1 | c.4291-9C>A | intron_variant | NP_001365546.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CC2D2A | ENST00000424120.6 | c.4438-9C>A | intron_variant | 5 | NM_001378615.1 | ENSP00000403465.1 |
Frequencies
GnomAD3 genomes 0.000506 AC: 77AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00141 AC: 220AN: 156338Hom.: 0 AF XY: 0.00142 AC XY: 117AN XY: 82358
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GnomAD4 exome AF: 0.000506 AC: 706AN: 1394330Hom.: 2 Cov.: 29 AF XY: 0.000532 AC XY: 366AN XY: 687850
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GnomAD4 genome 0.000506 AC: 77AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52AN XY: 74428
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 01, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 27, 2022 | Variant summary: CC2D2A c.4438-9C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 156338 control chromosomes (gnomAD), predominantly at a frequency of 0.0095 within the East Asian subpopulation in the gnomAD database. To our knowledge, no occurrence of c.4438-9C>A in individuals affected with CC2D2A-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Meckel syndrome, type 6 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Joubert syndrome 9 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not provided Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2021 | - - |
CC2D2A-related disorder Benign:1
| Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at