11-125961075-A-T

Variant names:

• chr11-125961075-A-T
• rs684535
• NM_001378964.1:c.3662T>A

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.3662T>A​(p.Ile1221Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,613,132 control chromosomes in the GnomAD database, including 403,270 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42774 hom., cov: 33)
  • Exomes 𝑓: 0.70 (360496 hom.)
• Consequence: CDON NM_001378964.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.447
• Publications: 29 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=4.3759915E-6).
• BP6: Variant 11-125961075-A-T is Benign according to our data. Variant chr11-125961075-A-T is described in ClinVar as Benign. ClinVar VariationId is 260799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 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.3662T>A	p.Ile1221Asn	missense	Exon 20 of 20	NP_001365893.1	Q4KMG0-2
	CDON	NM_001243597.3		c.3731T>A	p.Ile1244Asn	missense	Exon 20 of 20	NP_001230526.1
	CDON	NM_001441161.1		c.3731T>A	p.Ile1244Asn	missense	Exon 20 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.3662T>A	p.Ile1221Asn	missense	Exon 20 of 20	ENSP00000432901.2	Q4KMG0-2
	CDON	ENST00000392693.7	TSL:1	c.3731T>A	p.Ile1244Asn	missense	Exon 20 of 20	ENSP00000376458.3	Q4KMG0-1
	CDON	ENST00000263577.11	TSL:1	c.3662T>A	p.Ile1221Asn	missense	Exon 20 of 20	ENSP00000263577.7	Q4KMG0-2

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113304 AN: 151982 Hom.: 42730 Cov.: 33

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.528

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.745

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.744

GnomAD2 exomes AF: 0.732 AC: 183804 AN: 251040 AF XY: 0.727

Gnomad AFR exome AF: 0.844

Gnomad AMR exome AF: 0.784

Gnomad ASJ exome AF: 0.728

Gnomad EAS exome AF: 0.925

Gnomad FIN exome AF: 0.680

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.733

GnomAD4 exome AF: 0.700 AC: 1023018 AN: 1461030 Hom.: 360496 Cov.: 44 AF XY: 0.700 AC XY: 509011 AN XY: 726806

African (AFR) AF: 0.847 AC: 28363 AN: 33474

American (AMR) AF: 0.780 AC: 34890 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 19123 AN: 26126

East Asian (EAS) AF: 0.930 AC: 36908 AN: 39698

South Asian (SAS) AF: 0.722 AC: 62236 AN: 86202

European-Finnish (FIN) AF: 0.679 AC: 36276 AN: 53410

Middle Eastern (MID) AF: 0.714 AC: 4121 AN: 5768

European-Non Finnish (NFE) AF: 0.682 AC: 757535 AN: 1111266

Other (OTH) AF: 0.722 AC: 43566 AN: 60366

GnomAD4 genome AF: 0.746 AC: 113406 AN: 152102 Hom.: 42774 Cov.: 33 AF XY: 0.748 AC XY: 55582 AN XY: 74348

African (AFR) AF: 0.841 AC: 34909 AN: 41526

American (AMR) AF: 0.770 AC: 11779 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2560 AN: 3468

East Asian (EAS) AF: 0.923 AC: 4773 AN: 5170

South Asian (SAS) AF: 0.739 AC: 3534 AN: 4784

European-Finnish (FIN) AF: 0.694 AC: 7341 AN: 10572

Middle Eastern (MID) AF: 0.747 AC: 218 AN: 292

European-Non Finnish (NFE) AF: 0.680 AC: 46247 AN: 67970

Other (OTH) AF: 0.741 AC: 1566 AN: 2114

Alfa AF: 0.698 Hom.: 12090

Bravo AF: 0.759

TwinsUK AF: 0.675 AC: 2502

ALSPAC AF: 0.684 AC: 2637

ESP6500AA AF: 0.826 AC: 3635

ESP6500EA AF: 0.681 AC: 5855

ExAC AF: 0.731 AC: 88720

Asia WGS AF: 0.802 AC: 2788 AN: 3478

EpiCase AF: 0.695

EpiControl AF: 0.692

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)
-	-	1	Holoprosencephaly 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.7
DANN	Benign	0.48
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0000044	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.0	N
PhyloP100		0.45
PrimateAI	Benign	0.36	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MPC		0.17
ClinPred		0.0014	T
GERP RS		4.3
Varity_R		0.027
gMVP		0.071
Mutation Taster		=98/2	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: rs684535; hg19: chr11-125830970; COSMIC: COSV54998446; COSMIC: COSV54998446;