15-42729788-G-A

Variant names:

• chr15-42729788-G-A
• rs12594483
• NM_138477.4:c.2352+8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138477.4(CDAN1):​c.2352+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,610,632 control chromosomes in the GnomAD database, including 44,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (15611 hom., cov: 31)
  • Exomes 𝑓: 0.15 (28493 hom.)
• Consequence: CDAN1 NM_138477.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001100
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.299
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-42729788-G-A is Benign according to our data. Variant chr15-42729788-G-A is described in ClinVar as Benign. ClinVar VariationId is 262370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDAN1	NM_138477.4	c.2352+8C>T		splice_region_variant, intron_variant	Intron 16 of 27	ENST00000356231.4	NP_612486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDAN1	ENST00000356231.4	c.2352+8C>T		splice_region_variant, intron_variant	Intron 16 of 27	1	NM_138477.4	ENSP00000348564.3
CDAN1	ENST00000562465.5	n.345+8C>T		splice_region_variant, intron_variant	Intron 3 of 14	1		ENSP00000454246.1
CDAN1	ENST00000643434.1	n.*1530+8C>T		splice_region_variant, intron_variant	Intron 14 of 24			ENSP00000494699.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50396 AN: 151906 Hom.: 15548 Cov.: 31

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.282

GnomAD2 exomes AF: 0.209 AC: 52300 AN: 250466 AF XY: 0.203

Gnomad AFR exome AF: 0.832

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.153 AC: 223779 AN: 1458608 Hom.: 28493 Cov.: 33 AF XY: 0.156 AC XY: 113449 AN XY: 725720

African (AFR) AF: 0.851 AC: 28357 AN: 33330

American (AMR) AF: 0.139 AC: 6213 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5094 AN: 26088

East Asian (EAS) AF: 0.286 AC: 11361 AN: 39664

South Asian (SAS) AF: 0.311 AC: 26771 AN: 86012

European-Finnish (FIN) AF: 0.164 AC: 8761 AN: 53382

Middle Eastern (MID) AF: 0.183 AC: 1034 AN: 5650

European-Non Finnish (NFE) AF: 0.112 AC: 124450 AN: 1109550

Other (OTH) AF: 0.195 AC: 11738 AN: 60270

GnomAD4 genome AF: 0.332 AC: 50522 AN: 152024 Hom.: 15611 Cov.: 31 AF XY: 0.329 AC XY: 24449 AN XY: 74306

African (AFR) AF: 0.821 AC: 34022 AN: 41444

American (AMR) AF: 0.178 AC: 2718 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3468

East Asian (EAS) AF: 0.288 AC: 1486 AN: 5158

South Asian (SAS) AF: 0.307 AC: 1477 AN: 4816

European-Finnish (FIN) AF: 0.158 AC: 1668 AN: 10576

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.115 AC: 7801 AN: 67960

Other (OTH) AF: 0.279 AC: 588 AN: 2108

Alfa AF: 0.175 Hom.: 14743

Bravo AF: 0.353

Asia WGS AF: 0.325 AC: 1132 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.118

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2021

GeneDx

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 15, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.70
DANN	Benign	0.48
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
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: rs12594483; hg19: chr15-43021986;