NM_138477.4:c.1787A>G

Variant names:

• chr15-42731284-T-C
• rs12917189
• NM_138477.4:c.1787A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_138477.4(CDAN1):​c.1787A>G​(p.Gln596Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,613,810 control chromosomes in the GnomAD database, including 70,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (17757 hom., cov: 32)
  • Exomes 𝑓: 0.24 (52332 hom.)
• Consequence: CDAN1 NM_138477.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.17
• Publications: 41 publications found

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 Gene-Disease associations (from GenCC):

• anemia, congenital dyserythropoietic, type 1a

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital dyserythropoietic anemia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital dyserythropoietic anemia

  Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_138477.4
• BP4: Computational evidence support a benign effect (MetaRNN=5.55778E-7).
• BP6: Variant 15-42731284-T-C is Benign according to our data. Variant chr15-42731284-T-C is described in ClinVar as Benign. ClinVar VariationId is 21747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138477.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDAN1	NM_138477.4	MANE Select	c.1787A>G	p.Gln596Arg	missense	Exon 12 of 28	NP_612486.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDAN1	ENST00000356231.4	TSL:1 MANE Select	c.1787A>G	p.Gln596Arg	missense	Exon 12 of 28	ENSP00000348564.3
	CDAN1	ENST00000643434.1		n.*965A>G		non_coding_transcript_exon	Exon 10 of 25	ENSP00000494699.1
	CDAN1	ENST00000643434.1		n.*965A>G		3_prime_UTR	Exon 10 of 25	ENSP00000494699.1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59800 AN: 151922 Hom.: 17698 Cov.: 32

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.343

GnomAD2 exomes AF: 0.277 AC: 69759 AN: 251406 AF XY: 0.279

Gnomad AFR exome AF: 0.846

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.241 AC: 351814 AN: 1461770 Hom.: 52332 Cov.: 38 AF XY: 0.246 AC XY: 178665 AN XY: 727198

African (AFR) AF: 0.863 AC: 28883 AN: 33480

American (AMR) AF: 0.136 AC: 6091 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7876 AN: 26136

East Asian (EAS) AF: 0.246 AC: 9785 AN: 39700

South Asian (SAS) AF: 0.438 AC: 37798 AN: 86256

European-Finnish (FIN) AF: 0.255 AC: 13590 AN: 53394

Middle Eastern (MID) AF: 0.303 AC: 1746 AN: 5768

European-Non Finnish (NFE) AF: 0.206 AC: 229351 AN: 1111918

Other (OTH) AF: 0.276 AC: 16694 AN: 60394

GnomAD4 genome AF: 0.394 AC: 59910 AN: 152040 Hom.: 17757 Cov.: 32 AF XY: 0.391 AC XY: 29064 AN XY: 74310

African (AFR) AF: 0.835 AC: 34652 AN: 41476

American (AMR) AF: 0.197 AC: 3016 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1054 AN: 3470

East Asian (EAS) AF: 0.254 AC: 1312 AN: 5168

South Asian (SAS) AF: 0.426 AC: 2045 AN: 4802

European-Finnish (FIN) AF: 0.255 AC: 2692 AN: 10560

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14255 AN: 67970

Other (OTH) AF: 0.339 AC: 716 AN: 2110

Alfa AF: 0.268 Hom.: 24779

Bravo AF: 0.403

TwinsUK AF: 0.201 AC: 745

ALSPAC AF: 0.202 AC: 780

ESP6500AA AF: 0.819 AC: 3608

ESP6500EA AF: 0.210 AC: 1805

ExAC AF: 0.293 AC: 35595

Asia WGS AF: 0.356 AC: 1237 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.210

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24196372)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital dyserythropoietic anemia, type I Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Anemia, congenital dyserythropoietic, type 1a Benign:1

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.64
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.074	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.95	N
PhyloP100		2.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.25
Sift	Benign	0.51	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.087
ClinPred		0.0050	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.30
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12917189; hg19: chr15-43023482; COSMIC: COSV62331118; COSMIC: COSV62331118;