rs115533243

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378964.1(CDON):c.2623A>G(p.Ser875Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0152 in 1,599,236 control chromosomes in the GnomAD database, including 286 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. S875N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 43 hom., cov: 33)

Exomes 𝑓: 0.015 ( 243 hom. )

Consequence

CDON
NM_001378964.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.85

Publications

6 publications found

Variant links:

Genes affected

CDON (HGNC:17104): (cell adhesion associated, oncogene regulated) This gene encodes a cell surface receptor that is a member of the immunoglobulin superfamily. The encoded protein contains three fibronectin type III domains and five immunoglobulin-like C2-type domains. This protein is a member of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells and positively regulates myogenesis. [provided by RefSeq, Aug 2011]

CDON Gene-Disease associations (from GenCC):

holoprosencephaly 11
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
pituitary stalk interruption syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CDON links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006275445).

BP6

Variant 11-125994311-T-C is Benign according to our data. Variant chr11-125994311-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260789.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 = 0.0205 (3127/152304) while in subpopulation AFR AF = 0.0248 (1031/41574). AF 95% confidence interval is 0.0235. There are 43 homozygotes in GnomAd4. There are 1625 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDON	NM_001378964.1 link	c.2623A>G	p.Ser875Gly	missense_variant	Exon 14 of 20	ENST00000531738.6	NP_001365893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDON	ENST00000531738.6 link	c.2623A>G	p.Ser875Gly	missense_variant	Exon 14 of 20	1	NM_001378964.1	ENSP00000432901.2		Q4KMG0-2E9PN78

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3124

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0247

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.00538

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.0526

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0194

AC:

4859

AN:

250874

AF XY:

0.0195

show subpopulations

Gnomad AFR exome

AF:

0.0256

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0325

Gnomad EAS exome

AF:

0.00621

Gnomad FIN exome

AF:

0.0547

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0232

GnomAD4 exome

AF:

0.0146

AC:

21172

AN:

1446932

Hom.:

243

Cov.:

AF XY:

0.0148

AC XY:

10691

AN XY:

720930

show subpopulations

African (AFR)

AF:

0.0291

AC:

962

AN:

33110

American (AMR)

AF:

0.0131

AC:

587

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0308

AC:

801

AN:

26044

East Asian (EAS)

AF:

0.00348

AC:

138

AN:

39610

South Asian (SAS)

AF:

0.0203

AC:

1746

AN:

85948

European-Finnish (FIN)

AF:

0.0511

AC:

2727

AN:

53398

Middle Eastern (MID)

AF:

0.0344

AC:

196

AN:

5694

European-Non Finnish (NFE)

AF:

0.0118

AC:

12967

AN:

1098558

Other (OTH)

AF:

0.0175

AC:

1048

AN:

59870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

922

1844

2767

3689

4611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

496

992

1488

1984

2480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0205

AC:

3127

AN:

152304

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

1625

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0248

AC:

1031

AN:

41574

American (AMR)

AF:

0.0188

AC:

288

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3470

East Asian (EAS)

AF:

0.00540

AC:

AN:

5188

South Asian (SAS)

AF:

0.0189

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0526

AC:

558

AN:

10608

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0139

AC:

944

AN:

68024

Other (OTH)

AF:

0.0232

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

159

319

478

638

797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0146

Hom.:

Bravo

AF:

0.0192

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.0239

AC:

105

ESP6500EA

AF:

0.0151

AC:

130

ExAC

AF:

0.0186

AC:

2257

Asia WGS

AF:

0.0180

AC:

AN:

3474

EpiCase

AF:

0.0154

EpiControl

AF:

0.0171

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holoprosencephaly 11

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDON-related disorder

Benign:1

Apr 29, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

D;D;D

MetaRNN

Benign

0.0063

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.69

N;.;N

PhyloP100

5.8

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.7

D;N;D

REVEL

Benign

0.22

Sift

Benign

0.079

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.82

P;P;P

Vest4

0.31

MPC

0.32

ClinPred

0.024

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.44

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over