rs80338699

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_138477.4(CDAN1):​c.3389C>T​(p.Pro1130Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000266 in 1,614,028 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 (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CDAN1
NM_138477.4 missense

Scores

9
7
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 6.58
Variant links:
Genes affected
CDAN1 (HGNC:1713): (codanin 1) This gene encodes a protein that appears to play a role in nuclear envelope integrity, possibly related to microtubule attachments. Mutations in this gene cause congenital dyserythropoietic anemia type I, a disease resulting in morphological and functional abnormalities of erythropoiesis. [provided by RefSeq, Jul 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.913
PP5
Variant 15-42725550-G-A is Pathogenic according to our data. Variant chr15-42725550-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDAN1NM_138477.4 linkc.3389C>T p.Pro1130Leu missense_variant Exon 26 of 28 ENST00000356231.4 NP_612486.2 Q8IWY9-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDAN1ENST00000356231.4 linkc.3389C>T p.Pro1130Leu missense_variant Exon 26 of 28 1 NM_138477.4 ENSP00000348564.3 Q8IWY9-2

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251204
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.0000234
AC XY:
17
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000239
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 12, 2024This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1130 of the CDAN1 protein (p.Pro1130Leu). This variant is present in population databases (rs80338699, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of congenital dyserythropoietic anemia (PMID: 28102861, 29031773, 29676459, 29936674, 33401150). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3177). 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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicAug 04, 2023PP3, PM2_moderate, PM3, PS4 -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Anemia, congenital dyserythropoietic, type 1a Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneMay 14, 2019- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 05, 2024- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 27, 2021- -
Congenital dyserythropoietic anemia, type I Pathogenic:1Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2002- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.60
D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.86
D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-4.8
D
REVEL
Pathogenic
0.80
Sift
Benign
0.062
T
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.91
MVP
0.72
MPC
0.46
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.31
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338699; hg19: chr15-43017748; API