rs73410959

chr15-42736428-G-A

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.443C>T(p.Ala148Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,600,120 control chromosomes in the GnomAD database, including 1,497 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A148T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.058 (658 hom., cov: 32)
  • Exomes 𝑓: 0.013 (839 hom.)
• Consequence: CDAN1 NM_138477.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.12

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=0.0011544526).
• BP6: Variant 15-42736428-G-A is Benign according to our data. Variant chr15-42736428-G-A is described in ClinVar as [Benign]. Clinvar id is 262377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDAN1	NM_138477.4	c.443C>T	p.Ala148Val	missense_variant	2/28	ENST00000356231.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDAN1	ENST00000356231.4	c.443C>T	p.Ala148Val	missense_variant	2/28	1	NM_138477.4	P1
CDAN1	ENST00000643434.1	c.91-347C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8812 AN: 152036 Hom.: 656 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0581

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.0426

GnomAD3 exomes AF: 0.0250 AC: 5473 AN: 219152 Hom.: 289 AF XY: 0.0233 AC XY: 2808 AN XY: 120746

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.00979

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.0654

Gnomad SAS exome AF: 0.0285

Gnomad FIN exome AF: 0.000404

Gnomad NFE exome AF: 0.00521

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0126 AC: 18300 AN: 1447968 Hom.: 839 Cov.: 33 AF XY: 0.0127 AC XY: 9110 AN XY: 719152

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0323

Gnomad4 EAS exome AF: 0.0510

Gnomad4 SAS exome AF: 0.0290

Gnomad4 FIN exome AF: 0.000340

Gnomad4 NFE exome AF: 0.00420

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0580 AC: 8832 AN: 152152 Hom.: 658 Cov.: 32 AF XY: 0.0563 AC XY: 4186 AN XY: 74388

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.0218

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.0581

Gnomad4 SAS AF: 0.0271

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00510

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0298 Hom.: 51

Bravo AF: 0.0648

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.149 AC: 622

ESP6500EA AF: 0.00480 AC: 40

ExAC AF: 0.0260 AC: 3103

Asia WGS AF: 0.0480 AC: 167 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 29146883) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.17
Sift	Benign	0.23	T
Sift4G	Uncertain	0.035	D
Polyphen		0.091	B
Vest4		0.038
MPC		0.96
ClinPred		0.0022	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73410959; hg19: chr15-43028626; COSMIC: COSV51167757; COSMIC: COSV51167757;