rs114779238

chr15-42728236-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138477.4(CDAN1):c.2836C>T(p.Arg946Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,613,816 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R946Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (33 hom.)
• Consequence: CDAN1 NM_138477.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.33

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 (MetaRNN=0.008565098).
• BP6: Variant 15-42728236-G-A is Benign according to our data. Variant chr15-42728236-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42728236-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1775/152262) while in subpopulation AFR AF= 0.0382 (1586/41540). AF 95% confidence interval is 0.0366. There are 26 homozygotes in gnomad4. There are 872 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDAN1	NM_138477.4	c.2836C>T	p.Arg946Trp	missense_variant	21/28	ENST00000356231.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDAN1	ENST00000356231.4	c.2836C>T	p.Arg946Trp	missense_variant	21/28	1	NM_138477.4	P1
CDAN1	ENST00000562465.5	c.829C>T	p.Arg277Trp	missense_variant, NMD_transcript_variant	8/15	1
CDAN1	ENST00000643434.1	c.*2014C>T		3_prime_UTR_variant, NMD_transcript_variant	19/25

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1768 AN: 152144 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00398 AC: 999 AN: 250836 Hom.: 14 AF XY: 0.00324 AC XY: 439 AN XY: 135702

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000947

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000810

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00162 AC: 2366 AN: 1461554 Hom.: 33 Cov.: 32 AF XY: 0.00153 AC XY: 1115 AN XY: 727082

Gnomad4 AFR exome AF: 0.0375

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00501

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000426

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.0117 AC: 1775 AN: 152262 Hom.: 26 Cov.: 32 AF XY: 0.0117 AC XY: 872 AN XY: 74438

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00275 Hom.: 2

Bravo AF: 0.0137

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00455 AC: 552

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely 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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	CDAN1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital dyserythropoietic anemia, type I Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Anemia, congenital dyserythropoietic, type 1a Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0086	T
MetaSVM	Uncertain	-0.020	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.47
MPC		0.34
ClinPred		0.035	T
GERP RS		5.2
Varity_R		0.39
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114779238; hg19: chr15-43020434;