rs120074167

Positions:

• chr15-42730757-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CDAN1 NM_138477.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.34

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 (HGNC:):

ACMG classification

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, 0.965
• PP5: Variant 15-42730757-G-A is Pathogenic according to our data. Variant chr15-42730757-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3179.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	c.2015C>T	p.Pro672Leu	missense_variant	14/28	ENST00000356231.4	NP_612486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDAN1	ENST00000356231.4	c.2015C>T	p.Pro672Leu	missense_variant	14/28	1	NM_138477.4	ENSP00000348564.3
CDAN1	ENST00000562465.5	n.8C>T		non_coding_transcript_exon_variant	1/15	1		ENSP00000454246.1
CDAN1	ENST00000643434.1	n.*1193C>T		non_coding_transcript_exon_variant	12/25			ENSP00000494699.1
CDAN1	ENST00000643434.1	n.*1193C>T		3_prime_UTR_variant	12/25			ENSP00000494699.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152272 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 20 AN: 239248 Hom.: 0 AF XY: 0.0000994 AC XY: 13 AN XY: 130746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1459632 Hom.: 0 Cov.: 34 AF XY: 0.000143 AC XY: 104 AN XY: 725946

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74388

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000825 AC: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital dyserythropoietic anemia, type I Pathogenic:3

Pathogenic, no assertion criteria provided	curation	GeneReviews	Sep 01, 2011	- -
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	literature only	OMIM	Dec 01, 2002	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.83
Sift	Benign	0.76	T
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.91
MPC		0.46
ClinPred		0.87	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs120074167; hg19: chr15-43022955;