rs12594483

Positions:

• chr15-42729788-G-A
• chr15-42729788-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
CDAN1	NM_138477.4	c.2352+8C>T		splice_region_variant, intron_variant		ENST00000356231.4	NP_612486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDAN1	ENST00000356231.4	c.2352+8C>T		splice_region_variant, intron_variant		1	NM_138477.4	ENSP00000348564.3
CDAN1	ENST00000562465.5	n.345+8C>T		splice_region_variant, intron_variant		1		ENSP00000454246.1
CDAN1	ENST00000643434.1	n.*1530+8C>T		splice_region_variant, intron_variant				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

GnomAD3 exomes AF: 0.209 AC: 52300 AN: 250466 Hom.: 9559 AF XY: 0.203 AC XY: 27459 AN XY: 135370

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 SAS exome AF: 0.311

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

Gnomad4 AFR exome AF: 0.851

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.311

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.195

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

Gnomad4 AFR AF: 0.821

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.307

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.279

Alfa AF: 0.154 Hom.: 7740

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital dyserythropoietic anemia, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.70
DANN	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs12594483; hg19: chr15-43021986;