12-4299978-C-A
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_001759.4(CCND2):c.839C>A(p.Thr280Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,830 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T280A) has been classified as Pathogenic.
Frequency
Consequence
NM_001759.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCND2 | NM_001759.4 | c.839C>A | p.Thr280Asn | missense_variant | 5/5 | ENST00000261254.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCND2 | ENST00000261254.8 | c.839C>A | p.Thr280Asn | missense_variant | 5/5 | 1 | NM_001759.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152114Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727224
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74310
ClinVar
Submissions by phenotype
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 10, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to occur de novo in three patients with MPPH [PMID 24705253] - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Thr280Asn variant in CCND2 was identified by our study in one individual with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Trio exome analysis showed this variant to be de novo. The variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Thr280Asn variant in CCND2 has been reported in 5 individuals with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Trio analysis in the literature showed this variant to be de novo in 4 of those individuals and unknown in one individual (PMID: 24705253). In summary, the p.Thr280Asn variant is pathogenic based off of our findings and multiple de novo reports in the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong, PP3 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Dec 26, 2017 | [ACMG/AMP: PS2, PM1, PM2, PS4_Moderate, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Nov 09, 2021 | PS4_moderate, PM1, PM2, PP3 - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 27, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24705253, 32371413) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | CCND2: PM6:Strong, PM1, PM2, PM5, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 23, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr280 amino acid residue in CCND2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31056854). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt CCND2 protein function. ClinVar contains an entry for this variant (Variation ID: 143983). This missense change has been observed in individual(s) with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (PMID: 24705253). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 280 of the CCND2 protein (p.Thr280Asn). - |
Seizure Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Apr 05, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at