rs587777622
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_001759.4(CCND2):āc.842C>Gā(p.Pro281Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,802 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. P281L) has been classified as Pathogenic.
Frequency
Consequence
NM_001759.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCND2 | NM_001759.4 | c.842C>G | p.Pro281Arg | missense_variant | 5/5 | ENST00000261254.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCND2 | ENST00000261254.8 | c.842C>G | p.Pro281Arg | missense_variant | 5/5 | 1 | NM_001759.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152170Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461802Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727200
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
ClinVar
Submissions by phenotype
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 21, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CCND2 protein function (PMID: 24705253). This variant has been observed in individual(s) with clinical features of megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome (PMID: 24705253, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143985). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 281 of the CCND2 protein (p.Pro281Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. - |
CCND2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 15, 2023 | The CCND2 c.842C>G variant is predicted to result in the amino acid substitution p.Pro281Arg. This variant, as well as additional variants at the same amino acid (p.Pro281Ser, p.Pro281Leu, and p.Pro281Ala) have been been documented in individuals with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) (Mirzaa et al. 2014. PubMed ID:24705253; Supplementary Table 3, Patient 21, Helbig et al. 2016. PubMed ID: 26795593; Sameshima et al. 2020. PubMed ID: 31957131). Of note, these variants were documented as de novo in some cases (Mirzaa et al. 2014. PubMed ID:24705253; Supplementary Table 3, Patient 21, Helbig et al. 2016. PubMed ID: 26795593) and in others inheritance was not noted or not determined. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. While this variant may be causative, given the mosaic nature, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at