rs80338696

Variant summary

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

The NM_138477.4(CDAN1):c.2140C>T(p.Arg714Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,188 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 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CDAN1
NM_138477.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.33

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

PP5

Variant 15-42730632-G-A is Pathogenic according to our data. Variant chr15-42730632-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDAN1	NM_138477.4 linkuse as main transcript	c.2140C>T	p.Arg714Trp	missense_variant	14/28	ENST00000356231.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDAN1	ENST00000356231.4 linkuse as main transcript	c.2140C>T	p.Arg714Trp	missense_variant	14/28	1	NM_138477.4	P1	Q8IWY9-2
CDAN1	ENST00000562465.5 linkuse as main transcript	c.133C>T	p.Arg45Trp	missense_variant, NMD_transcript_variant	1/15	1
CDAN1	ENST00000643434.1 linkuse as main transcript	c.*1318C>T		3_prime_UTR_variant, NMD_transcript_variant	12/25

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

251018

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000363

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 08, 2020	PS3, PS4_Moderate, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CDAN1 function (PMID: 22407294). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 21748). This variant is also known as 2254C>T (R712W). This missense change has been observed in individual(s) with congenital dyserythropoietic anemia type 1 (PMID: 12434312, 29031773, 29668551, 29901818, 32160409). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs80338696, gnomAD 0.05%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 714 of the CDAN1 protein (p.Arg714Trp). -

Congenital dyserythropoietic anemia, type I

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 06, 2017

The CDAN1 c.2140C>T (p.Arg714Trp) missense variant has been reported in at least three studies in which it is found in a total of two patients with congenital dyserythropoietic anemia (CDA) in a compound heterozygous state (Dgany et al. 2002; Ru et al. 2008). The p.Arg714Trp variant was reported in one of 82 controls in a heterozygous state and is reported at a frequency of 0.00052 in the East Asian population of the Genome Aggregation Database. Functional data from Ask et al. (2012) suggests p.Arg714Trp alters protein function. Using an immunoprecipitation assay and cell localization nuclear staining assay, Ask et al. (2012) showed that the p.Arg714Trp variant impairs binding to a CDAN1 cofactor and inhibits sequestration of the cofactor in the cytoplasm. Further, a complementation assay showed the p.Arg714Trp variant is unable to rescue CDAN1 depletion. Based on the evidence, the p.Arg714Trp variant is classified as likely pathogenic for congenital dyserythropoietic anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.26

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.67

MVP

0.89

MPC

0.46

ClinPred

0.82

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.29

gMVP

0.57

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

Other links and lift over