dbSNP rs35665264: CDON:p.Pro351Ala (chr11-126015388-G-C) – ACMG Classification: Benign (-20 pts)

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.1051C>G(p.Pro351Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00278 in 1,614,146 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 56 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 31 hom. )

Consequence

CDON
NM_001378964.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.10

Publications

7 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: Illumina, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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=0.009128988).

BP6

Variant 11-126015388-G-C is Benign according to our data. Variant chr11-126015388-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260781.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 = 0.0147 (2233/152268) while in subpopulation AFR AF = 0.0502 (2083/41528). AF 95% confidence interval is 0.0484. There are 56 homozygotes in GnomAd4. There are 1072 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2233 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDON	NM_001378964.1	MANE Select	c.1051C>G	p.Pro351Ala	missense	Exon 7 of 20	NP_001365893.1	Q4KMG0-2
CDON	NM_001243597.3		c.1051C>G	p.Pro351Ala	missense	Exon 7 of 20	NP_001230526.1
CDON	NM_001441161.1		c.1051C>G	p.Pro351Ala	missense	Exon 7 of 20	NP_001428090.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDON	ENST00000531738.6	TSL:1 MANE Select	c.1051C>G	p.Pro351Ala	missense	Exon 7 of 20	ENSP00000432901.2	Q4KMG0-2
CDON	ENST00000392693.7	TSL:1	c.1051C>G	p.Pro351Ala	missense	Exon 7 of 20	ENSP00000376458.3	Q4KMG0-1
CDON	ENST00000263577.11	TSL:1	c.1051C>G	p.Pro351Ala	missense	Exon 7 of 20	ENSP00000263577.7	Q4KMG0-2

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2230

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0502

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00380

AC:

955

AN:

251304

AF XY:

0.00289

show subpopulations

Gnomad AFR exome

AF:

0.0500

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00154

AC:

2249

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

973

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0490

AC:

1641

AN:

33480

American (AMR)

AF:

0.00295

AC:

132

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000244

AC:

271

AN:

1112004

Other (OTH)

AF:

0.00305

AC:

184

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

129

257

386

514

643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0147

AC:

2233

AN:

152268

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1072

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0502

AC:

2083

AN:

41528

American (AMR)

AF:

0.00738

AC:

113

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68030

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

210

316

421

526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00244

Hom.:

Bravo

AF:

0.0170

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0547

AC:

241

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00481

AC:

584

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holoprosencephaly 11 (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.5

PhyloP100

6.1

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.46

Sift

Uncertain

0.019

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.56

MVP

0.87

MPC

0.49

ClinPred

0.024

GERP RS

5.4

Varity_R

0.24

gMVP

0.59

Mutation Taster

=86/14

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over