rs115533243

Variant names:

• chr11-125994311-T-C
• rs115533243
• NM_001378964.1:c.2623A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.85
• Publications: 6 publications found

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: Illumina, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pituitary stalk interruption syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378964.1. 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
	CDON	NM_001378964.1	MANE Select	c.2623A>G	p.Ser875Gly	missense	Exon 14 of 20	NP_001365893.1	Q4KMG0-2
	CDON	NM_001243597.3		c.2623A>G	p.Ser875Gly	missense	Exon 14 of 20	NP_001230526.1
	CDON	NM_001441161.1		c.2623A>G	p.Ser875Gly	missense	Exon 14 of 20	NP_001428090.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDON	ENST00000531738.6	TSL:1 MANE Select	c.2623A>G	p.Ser875Gly	missense	Exon 14 of 20	ENSP00000432901.2	Q4KMG0-2
	CDON	ENST00000392693.7	TSL:1	c.2623A>G	p.Ser875Gly	missense	Exon 14 of 20	ENSP00000376458.3	Q4KMG0-1
	CDON	ENST00000263577.11	TSL:1	c.2623A>G	p.Ser875Gly	missense	Exon 14 of 20	ENSP00000263577.7	Q4KMG0-2

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3124 AN: 152186 Hom.: 43 Cov.: 33

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

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.: 27 AF XY: 0.0148 AC XY: 10691 AN XY: 720930

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

GnomAD4 genome AF: 0.0205 AC: 3127 AN: 152304 Hom.: 43 Cov.: 33 AF XY: 0.0218 AC XY: 1625 AN XY: 74474

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: 28 AN: 5188

South Asian (SAS) AF: 0.0189 AC: 91 AN: 4824

European-Finnish (FIN) AF: 0.0526 AC: 558 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0139 AC: 944 AN: 68024

Other (OTH) AF: 0.0232 AC: 49 AN: 2116

Alfa AF: 0.0146 Hom.: 69

Bravo AF: 0.0192

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.0239 AC: 105

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0186 AC: 2257

Asia WGS AF: 0.0180 AC: 64 AN: 3474

EpiCase AF: 0.0154

EpiControl AF: 0.0171

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Holoprosencephaly 11 (3)
-	-	2	not provided (2)
-	-	1	CDON-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.22
Sift	Benign	0.079	T
Sift4G	Benign	0.17	T
Polyphen		0.82	P
Vest4		0.31
MPC		0.32
ClinPred		0.024	T
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)

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

Other links and lift over

dbSNP: rs115533243; hg19: chr11-125864206;