rs120074167
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_138477.4(CDAN1):c.2015C>T(p.Pro672Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000158 in 1,611,904 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P672P) has been classified as Likely benign.
Frequency
Consequence
NM_138477.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDAN1 | NM_138477.4 | c.2015C>T | p.Pro672Leu | missense_variant | 14/28 | ENST00000356231.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDAN1 | ENST00000356231.4 | c.2015C>T | p.Pro672Leu | missense_variant | 14/28 | 1 | NM_138477.4 | P1 | |
CDAN1 | ENST00000562465.5 | c.8C>T | p.Pro3Leu | missense_variant, NMD_transcript_variant | 1/15 | 1 | |||
CDAN1 | ENST00000643434.1 | c.*1193C>T | 3_prime_UTR_variant, NMD_transcript_variant | 12/25 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152272Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000836 AC: 20AN: 239248Hom.: 0 AF XY: 0.0000994 AC XY: 13AN XY: 130746
GnomAD4 exome AF: 0.000160 AC: 234AN: 1459632Hom.: 0 Cov.: 34 AF XY: 0.000143 AC XY: 104AN XY: 725946
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152272Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74388
ClinVar
Submissions by phenotype
Congenital dyserythropoietic anemia, type I Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jan 04, 2018 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Sep 01, 2011 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 672 of the CDAN1 protein (p.Pro672Leu). This variant is present in population databases (rs120074167, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital dyserythropoietic anemia type I (PMID: 12434312, 31900952, 33401150). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 2129C>T, Pro671Leu. ClinVar contains an entry for this variant (Variation ID: 3179). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 29, 2021 | PS4, PM1 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27432187, 20301759, 16098079, 31900952, 32518175, 29797310, 23065504, 12434312, 35417566, 28102861, 33401150) - |
Anemia, congenital dyserythropoietic, type 1a Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 03, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 01, 2023 | The CDAN1 c.2015C>T; p.Pro672Leu variant (rs120074167) is reported as a compound heterozygous variant with other pathogenic CDAN1 variants in the literature in several individuals affected with congenital dyserythropoietic anemia (CDA) type I (Dgany 2002, Garcia-Zamora 2020, Muramatsu 2017, Niss 2021, Olijnik 2021, Scott 2022). This variant is also reported in ClinVar (Variation ID: 3179). This variant is found predominantly in the non-Finnish European population with an allele frequency of 0.01% (17/121,360 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.826). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Dgany O et al. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. Am J Hum Genet. 2002 Dec. PMID: 12434312 Garcia-Zamora E et al. Congenital dyserythropoietic anaemia type I with nails and bone abnormalities. Clinical and experimental dermatology. 2020 Jun. PMID: 31900952 Muramatsu H et al. Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. Genet Med. 2017 Jul. PMID: 28102861 Niss O et al. Congenital dyserythropoietic anemia type I: First report from the Congenital Dyserythropoietic Anemia Registry of North America (CDAR). Blood Cells Mol Dis. 2021 Mar. PMID: 33401150 Olijnik AA et al. Genetic and functional insights into CDA-I prevalence and pathogenesis. J Med Genet. 2021 Mar. PMID: 32518175 Scott C et al. Functional impairment of erythropoiesis in Congenital Dyserythropoietic Anaemia type I arises at the progenitor level. Br J Haematol. 2022 Jul. PMID: 35417566 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 28, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at