rs3740912

Variant names:

• chr11-126021374-C-T
• rs3740912
• NM_001378964.1:c.223G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-126021374-C-T
• chr11-126021374-C-G

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.223G>A​(p.Val75Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,613,614 control chromosomes in the GnomAD database, including 262,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V75V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.63 (31463 hom., cov: 31)
  • Exomes 𝑓: 0.56 (230565 hom.)
• Consequence: CDON NM_001378964.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.22
• Publications: 39 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=9.736624E-7).
• BP6: Variant 11-126021374-C-T is Benign according to our data. Variant chr11-126021374-C-T is described in ClinVar as Benign. ClinVar VariationId is 95752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.807 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.223G>A	p.Val75Ile	missense	Exon 3 of 20	NP_001365893.1	Q4KMG0-2
	CDON	NM_001243597.3		c.223G>A	p.Val75Ile	missense	Exon 3 of 20	NP_001230526.1
	CDON	NM_001441161.1		c.223G>A	p.Val75Ile	missense	Exon 3 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.223G>A	p.Val75Ile	missense	Exon 3 of 20	ENSP00000432901.2	Q4KMG0-2
	CDON	ENST00000392693.7	TSL:1	c.223G>A	p.Val75Ile	missense	Exon 3 of 20	ENSP00000376458.3	Q4KMG0-1
	CDON	ENST00000263577.11	TSL:1	c.223G>A	p.Val75Ile	missense	Exon 3 of 20	ENSP00000263577.7	Q4KMG0-2

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95653 AN: 151916 Hom.: 31412 Cov.: 31

Gnomad AFR AF: 0.814

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.572

GnomAD2 exomes AF: 0.554 AC: 139325 AN: 251292 AF XY: 0.551

Gnomad AFR exome AF: 0.820

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.555

GnomAD4 exome AF: 0.558 AC: 814980 AN: 1461580 Hom.: 230565 Cov.: 49 AF XY: 0.556 AC XY: 404346 AN XY: 727082

African (AFR) AF: 0.825 AC: 27619 AN: 33472

American (AMR) AF: 0.508 AC: 22736 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 15816 AN: 26134

East Asian (EAS) AF: 0.303 AC: 12017 AN: 39696

South Asian (SAS) AF: 0.528 AC: 45505 AN: 86250

European-Finnish (FIN) AF: 0.628 AC: 33533 AN: 53420

Middle Eastern (MID) AF: 0.548 AC: 3160 AN: 5768

European-Non Finnish (NFE) AF: 0.558 AC: 620209 AN: 1111740

Other (OTH) AF: 0.569 AC: 34385 AN: 60384

GnomAD4 genome AF: 0.630 AC: 95762 AN: 152034 Hom.: 31463 Cov.: 31 AF XY: 0.628 AC XY: 46668 AN XY: 74286

African (AFR) AF: 0.815 AC: 33786 AN: 41476

American (AMR) AF: 0.560 AC: 8559 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2052 AN: 3470

East Asian (EAS) AF: 0.319 AC: 1648 AN: 5160

South Asian (SAS) AF: 0.522 AC: 2516 AN: 4822

European-Finnish (FIN) AF: 0.645 AC: 6803 AN: 10540

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.564 AC: 38363 AN: 67972

Other (OTH) AF: 0.571 AC: 1206 AN: 2112

Alfa AF: 0.574 Hom.: 127501

Bravo AF: 0.628

TwinsUK AF: 0.552 AC: 2045

ALSPAC AF: 0.547 AC: 2109

ESP6500AA AF: 0.802 AC: 3530

ESP6500EA AF: 0.565 AC: 4857

ExAC AF: 0.557 AC: 67644

Asia WGS AF: 0.489 AC: 1699 AN: 3478

EpiCase AF: 0.559

EpiControl AF: 0.558

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Holoprosencephaly 11 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.7
DANN	Benign	0.20
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.65	N
PhyloP100		1.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.058
Sift	Benign	0.79	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.024
MPC		0.081
ClinPred		0.0019	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs3740912; hg19: chr11-125891269; COSMIC: COSV54996165; COSMIC: COSV54996165;