Variant rs80338697 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_138477.4(CDAN1):c.3124C>T(p.Arg1042Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,445,592 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: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CDAN1
NM_138477.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 1.70

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]

CDAN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 15-42726390-G-A is Pathogenic according to our data. Variant chr15-42726390-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDAN1	NM_138477.4 linkuse as main transcript	c.3124C>T	p.Arg1042Trp	missense_variant	24/28	ENST00000356231.4	NP_612486.2	Q8IWY9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDAN1	ENST00000356231.4 linkuse as main transcript	c.3124C>T	p.Arg1042Trp	missense_variant	24/28	1	NM_138477.4	ENSP00000348564.3		Q8IWY9-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000909

AC:

AN:

219914

Hom.:

AF XY:

0.00000840

AC XY:

AN XY:

119116

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.0000604

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1445592

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

717618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000777

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000127

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000334

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, congenital dyserythropoietic, type 1a

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Bedouin population -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The homozygous p.Arg1042Trp variant in CDAN1 was identified by our study in 1 individual with anemia, congenital dyserythropoietic, type 1a. The variant has been reported in at least 10 Israeli Bedouin individuals with anemia, congenital dyserythropoietic, type 1a (PMID: 12434312, 18081704), segregated with disease in at least 4 affected relatives from at least one family (PMID: 12434312), and has been identified in 0.01% (1/9396) of Ashkenazi Jewish and 0.006% (1/16548) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338697). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 3176) as pathogenic by OMIM, GeneReviews, and CeGaT Praxis fuer Humangenetik Tuebingen. In vitro functional studies provide some evidence that the p.Arg1042Trp variant may impact protein function (PMID: 22407294). However, these types of assays may not accurately represent biological function. 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 presence of this variant in at least 10 affected homozygotes, and in at least 10 individuals with anemia, congenital dyserythropoietic, type 1a increases the likelihood that the p.Arg1042Trp variant is pathogenic (PMID: 12434312, 18081704). Multiple variants in the same region as p.Arg1042Trp have been reported in association with disease, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 18081704). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_strong, PM3, PM1_supporting, PS3_supporting, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The missense variant c.3124C>T (p.Arg1042Trp) in the CDAN1 gene has been reported previously in homozygous state in multiple individuals affected with Congenital dyserythropoietic anaemia. This variant is considered as a founder mutation in Israeli Bedouin patients. In vitro, functional studies provide some evidence that the p.Arg1042Trp variant may impact protein function (Ask et al., 2012; Tamary et al., 2008; Dgany et al., 2002). This variant is reported with the allele frequency (0.0009%) in the gnomAD. It is submitted to ClinVar with varying interpretations as Pathogenic/Likely Pathogenic. The amino acid Arginine at position 1042 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg1042Trp in CDAN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Congenital dyserythropoietic anemia, type I

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2002

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.81

MutPred

0.84

Loss of solvent accessibility (P = 6e-04);

MVP

0.75

MPC

0.46

ClinPred

0.94

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.74

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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