rs114866803

Variant names:

• chr11-126010583-C-T
• rs114866803
• NM_001378964.1:c.1310G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001378964.1(CDON):​c.1310G>A​(p.Arg437His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,614,074 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: CDON NM_001378964.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.07
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
• pituitary stalk interruption syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016666144).
• BP6: Variant 11-126010583-C-T is Benign according to our data. Variant chr11-126010583-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 539750.
• BS2: High AC in GnomAd4 at 280 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.1310G>A	p.Arg437His	missense	Exon 8 of 20	NP_001365893.1
	CDON	NM_001243597.3		c.1310G>A	p.Arg437His	missense	Exon 8 of 20	NP_001230526.1
	CDON	NM_001441161.1		c.1310G>A	p.Arg437His	missense	Exon 8 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.1310G>A	p.Arg437His	missense	Exon 8 of 20	ENSP00000432901.2
	CDON	ENST00000392693.7	TSL:1	c.1310G>A	p.Arg437His	missense	Exon 8 of 20	ENSP00000376458.3
	CDON	ENST00000263577.11	TSL:1	c.1310G>A	p.Arg437His	missense	Exon 8 of 20	ENSP00000263577.7

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000533 AC: 133 AN: 249614 AF XY: 0.000429

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000983

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000251 AC: 367 AN: 1461800 Hom.: 1 Cov.: 31 AF XY: 0.000221 AC XY: 161 AN XY: 727208

African (AFR) AF: 0.00696 AC: 233 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1111924

Other (OTH) AF: 0.000530 AC: 32 AN: 60396

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74466

African (AFR) AF: 0.00636 AC: 264 AN: 41540

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000823 Hom.: 0

Bravo AF: 0.00209

ESP6500AA AF: 0.00682 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Holoprosencephaly 11 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.084
Sift	Benign	0.54	T
Sift4G	Benign	0.41	T
Polyphen		0.094	B
Vest4		0.17
MVP		0.61
MPC		0.15
ClinPred		0.0039	T
GERP RS		2.4
Varity_R		0.034
gMVP		0.48
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs114866803; hg19: chr11-125880478;