15-42725228-T-G

Position:

• chr15-42725228-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138477.4(CDAN1):​c.3474A>C​(p.Leu1158Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,613,572 control chromosomes in the GnomAD database, including 75,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (18329 hom., cov: 32)
  • Exomes 𝑓: 0.26 (57421 hom.)
• Consequence: CDAN1 NM_138477.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.474

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 15-42725228-T-G is Benign according to our data. Variant chr15-42725228-T-G is described in ClinVar as [Benign]. Clinvar id is 262376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42725228-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.474 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDAN1	NM_138477.4	c.3474A>C	p.Leu1158Leu	synonymous_variant	27/28	ENST00000356231.4	NP_612486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDAN1	ENST00000356231.4	c.3474A>C	p.Leu1158Leu	synonymous_variant	27/28	1	NM_138477.4	ENSP00000348564.3

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61627 AN: 151974 Hom.: 18268 Cov.: 32

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.356

GnomAD3 exomes AF: 0.289 AC: 72666 AN: 251402 Hom.: 14168 AF XY: 0.290 AC XY: 39445 AN XY: 135876

Gnomad AFR exome AF: 0.850

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.261

Gnomad SAS exome AF: 0.436

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.256 AC: 374211 AN: 1461480 Hom.: 57421 Cov.: 33 AF XY: 0.261 AC XY: 189605 AN XY: 727086

Gnomad4 AFR exome AF: 0.867

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.320

Gnomad4 EAS exome AF: 0.248

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.406 AC: 61743 AN: 152092 Hom.: 18329 Cov.: 32 AF XY: 0.402 AC XY: 29905 AN XY: 74348

Gnomad4 AFR AF: 0.840

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.352

Alfa AF: 0.242 Hom.: 6425

Bravo AF: 0.418

Asia WGS AF: 0.359 AC: 1249 AN: 3478

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 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 13, 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 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.0
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs16957091; hg19: chr15-43017426; COSMIC: COSV51900020; COSMIC: COSV51900020;