chr11-126001820-G-A

Variant names:

• chr11-126001820-G-A
• rs12274923
• NM_001378964.1:c.2057C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378964.1(CDON):​c.2057C>T​(p.Ala686Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,595,034 control chromosomes in the GnomAD database, including 26,783 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. A686S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2116 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24667 hom.)
• Consequence: CDON NM_001378964.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.53
• Publications: 24 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=0.001748234).
• BP6: Variant 11-126001820-G-A is Benign according to our data. Variant chr11-126001820-G-A is described in ClinVar as Benign. ClinVar VariationId is 260785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

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.2057C>T	p.Ala686Val	missense	Exon 11 of 20	NP_001365893.1	Q4KMG0-2
	CDON	NM_001243597.3		c.2057C>T	p.Ala686Val	missense	Exon 11 of 20	NP_001230526.1
	CDON	NM_001441161.1		c.2057C>T	p.Ala686Val	missense	Exon 11 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.2057C>T	p.Ala686Val	missense	Exon 11 of 20	ENSP00000432901.2	Q4KMG0-2
	CDON	ENST00000392693.7	TSL:1	c.2057C>T	p.Ala686Val	missense	Exon 11 of 20	ENSP00000376458.3	Q4KMG0-1
	CDON	ENST00000263577.11	TSL:1	c.2057C>T	p.Ala686Val	missense	Exon 11 of 20	ENSP00000263577.7	Q4KMG0-2

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24260 AN: 152022 Hom.: 2111 Cov.: 32

Gnomad AFR AF: 0.0935

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0708

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.167 AC: 41836 AN: 251156 AF XY: 0.167

Gnomad AFR exome AF: 0.0890

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.0710

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.180 AC: 259760 AN: 1442894 Hom.: 24667 Cov.: 30 AF XY: 0.179 AC XY: 128853 AN XY: 718742

African (AFR) AF: 0.0838 AC: 2792 AN: 33302

American (AMR) AF: 0.158 AC: 7046 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5626 AN: 25992

East Asian (EAS) AF: 0.0739 AC: 2928 AN: 39644

South Asian (SAS) AF: 0.140 AC: 12055 AN: 85900

European-Finnish (FIN) AF: 0.219 AC: 11668 AN: 53366

Middle Eastern (MID) AF: 0.129 AC: 741 AN: 5744

European-Non Finnish (NFE) AF: 0.189 AC: 206808 AN: 1094496

Other (OTH) AF: 0.169 AC: 10096 AN: 59760

GnomAD4 genome AF: 0.160 AC: 24289 AN: 152140 Hom.: 2116 Cov.: 32 AF XY: 0.159 AC XY: 11855 AN XY: 74374

African (AFR) AF: 0.0935 AC: 3881 AN: 41514

American (AMR) AF: 0.163 AC: 2495 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3468

East Asian (EAS) AF: 0.0704 AC: 364 AN: 5172

South Asian (SAS) AF: 0.139 AC: 669 AN: 4818

European-Finnish (FIN) AF: 0.213 AC: 2248 AN: 10564

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13271 AN: 67996

Other (OTH) AF: 0.147 AC: 311 AN: 2114

Alfa AF: 0.172 Hom.: 6974

Bravo AF: 0.150

TwinsUK AF: 0.198 AC: 733

ALSPAC AF: 0.190 AC: 732

ESP6500AA AF: 0.102 AC: 451

ESP6500EA AF: 0.192 AC: 1653

ExAC AF: 0.163 AC: 19809

Asia WGS AF: 0.133 AC: 464 AN: 3478

EpiCase AF: 0.181

EpiControl AF: 0.183

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Holoprosencephaly 11 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.17
Sift	Benign	0.082	T
Sift4G	Benign	0.084	T
Polyphen		0.95	P
Vest4		0.096
MPC		0.10
ClinPred		0.017	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.30
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12274923; hg19: chr11-125871715; COSMIC: COSV99074608; COSMIC: COSV99074608;