rs145983470

chr11-126001826-G-C

Variant summary

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

The NM_001378964.1(CDON):c.2051C>G(p.Thr684Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00767 in 1,607,342 control chromosomes in the GnomAD database, including 66 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (62 hom.)
• Consequence: CDON NM_001378964.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.22

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008403778).
• BP6: Variant 11-126001826-G-C is Benign according to our data. Variant chr11-126001826-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 303504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-126001826-G-C is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00605 (921/152252) while in subpopulation NFE AF= 0.00813 (553/68022). AF 95% confidence interval is 0.00757. There are 4 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 921 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDON	NM_001378964.1	c.2051C>G	p.Thr684Ser	missense_variant	11/20	ENST00000531738.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDON	ENST00000531738.6	c.2051C>G	p.Thr684Ser	missense_variant	11/20	1	NM_001378964.1	P1

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 921 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00813

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00693 AC: 1741 AN: 251240 Hom.: 9 AF XY: 0.00702 AC XY: 953 AN XY: 135776

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.0191

Gnomad NFE exome AF: 0.00840

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00784 AC: 11401 AN: 1455090 Hom.: 62 Cov.: 29 AF XY: 0.00775 AC XY: 5616 AN XY: 724356

Gnomad4 AFR exome AF: 0.000988

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00299

Gnomad4 FIN exome AF: 0.0207

Gnomad4 NFE exome AF: 0.00828

Gnomad4 OTH exome AF: 0.00696

GnomAD4 genome AF: 0.00605 AC: 921 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00640 AC XY: 476 AN XY: 74432

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.00813

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00866 Hom.: 1

Bravo AF: 0.00496

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00682 AC: 828

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00765

ClinVar

Significance: Benign/Likely 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	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CDON: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 09, 2017	- -

Holoprosencephaly 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

CDON-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2019

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	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.043	D;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.44	B;B;P
Vest4		0.14
MutPred		0.19		Loss of methylation at K682 (P = 0.0823);.;Loss of methylation at K682 (P = 0.0823);
MVP		0.79
MPC		0.093
ClinPred		0.014	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.20

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: rs145983470; hg19: chr11-125871721; COSMIC: COSV99700488; COSMIC: COSV99700488;