rs114779238

Variant names:

• chr15-42728236-G-A
• rs114779238
• NM_138477.4:c.2836C>T

Variant summary

Our verdict is Benign. The variant received -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:7
• Conservation: PhyloP100: 2.33
• Publications: 9 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 (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 Benign/Likely_benign. ClinVar VariationId is 235430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDAN1	NM_138477.4	MANE Select	c.2836C>T	p.Arg946Trp	missense	Exon 21 of 28	NP_612486.2	Q8IWY9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDAN1	ENST00000356231.4	TSL:1 MANE Select	c.2836C>T	p.Arg946Trp	missense	Exon 21 of 28	ENSP00000348564.3	Q8IWY9-2
	CDAN1	ENST00000562465.5	TSL:1	n.829C>T		non_coding_transcript_exon	Exon 8 of 15	ENSP00000454246.1	H3BM60
	CDAN1	ENST00000913682.1		c.2839C>T	p.Arg947Trp	missense	Exon 21 of 28	ENSP00000583741.1

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

GnomAD2 exomes AF: 0.00398 AC: 999 AN: 250836 AF XY: 0.00324

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 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

African (AFR) AF: 0.0375 AC: 1256 AN: 33476

American (AMR) AF: 0.00360 AC: 161 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 131 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00122 AC: 105 AN: 86256

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53146

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5766

European-Non Finnish (NFE) AF: 0.000426 AC: 474 AN: 1111960

Other (OTH) AF: 0.00358 AC: 216 AN: 60390

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

African (AFR) AF: 0.0382 AC: 1586 AN: 41540

American (AMR) AF: 0.00627 AC: 96 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68026

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00422 Hom.: 21

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Anemia, congenital dyserythropoietic, type 1a (1)
-	-	1	Congenital dyserythropoietic anemia, type I (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.3
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
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs114779238; hg19: chr15-43020434;