15-42736715-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_138477.4(CDAN1):c.156C>G(p.Phe52Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,560,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

CDAN1
NM_138477.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.10

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-42736715-G-C is Pathogenic according to our data. Variant chr15-42736715-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42736715-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDAN1	NM_138477.4 link	c.156C>G	p.Phe52Leu	missense_variant	Exon 2 of 28	ENST00000356231.4	NP_612486.2	Q8IWY9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDAN1	ENST00000356231.4 link	c.156C>G	p.Phe52Leu	missense_variant	Exon 2 of 28	1	NM_138477.4	ENSP00000348564.3	Q8IWY9-2
CDAN1	ENST00000563260.1 link	c.132C>G	p.Phe44Leu	missense_variant	Exon 2 of 2	3		ENSP00000455536.1	H3BPZ6
CDAN1	ENST00000643434.1 link	n.90+298C>G		intron_variant	Intron 1 of 24			ENSP00000494699.1	A0A2R8Y5C2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000942

AC:

AN:

169766

Hom.:

AF XY:

0.000127

AC XY:

AN XY:

94326

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000318

AC:

448

AN:

1408716

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

208

AN XY:

698320

show subpopulations

Gnomad4 AFR exome

AF:

0.0000337

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000400

Gnomad4 OTH exome

AF:

0.000189

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000871

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Nov 30, 2021

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant segregates with disease in at least one family (PMID: 33401150, 16098079, 27432187). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein. This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Jul 25, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F52L variant in the CDAN1 gene has been reported previously in association with congenital dyserythropoietic anemia in affected individuals who were heterozygous for the F52L variant and another CDAN1 variant; however, parental testing information was not provided to determine if the variants were in trans (Tamary et al., 2005; Roy et al., 2016). The F52L variant was not observed in approximately 5,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, though the average read depth at this position was low (5X). The F52L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The F52L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 52 of the CDAN1 protein (p.Phe52Leu). This variant is present in population databases (rs80338694, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive dyserythropoietic anemia (PMID: 27432187; Invitae). 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: 21746). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -

Feb 20, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PP5, PM1, PM2, PM3 -

Anemia, congenital dyserythropoietic, type 1a

Pathogenic:3

May 21, 2019

Centogene AG - the Rare Disease Company

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital dyserythropoietic anemia, type I

Pathogenic:1

Jul 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDAN1 c.156C>G (p.Phe52Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 169766 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDAN1 causing Congenital dyserythropoietic anemia, type I, allowing no conclusion about variant significance. c.156C>G has been reported in the literature in individuals affected with Congenital dyserythropoietic anemia, type I (Tamary_2005, Roy_2016, Maron_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37432431, 33401150, 27432187, 16098079). ClinVar contains an entry for this variant (Variation ID: 21746). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

CDAN1-related disorder

Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDAN1 c.156C>G variant is predicted to result in the amino acid substitution p.Phe52Leu. This variant has been reported to be causative for congenital dyserythropoietic anemia type I (Tamary et al. 2005. PubMed ID: 16098079; Roy et al. 2016. PubMed ID: 27432187; Niss et al. 2020. PubMed ID: 33401150). This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.84

T;D

M_CAP

Pathogenic

0.50

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;.

Vest4

0.40

MutPred

0.45

Gain of MoRF binding (P = 0.1159);.;

MVP

0.71

MPC

1.0

ClinPred

0.74

GERP RS

4.5

Varity_R

0.44

gMVP

0.50

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