Genetic Variant CDH22:p.Ser763Leu (chr20-46174705-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021248.3(CDH22):c.2288C>T(p.Ser763Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,557,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CDH22
NM_021248.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.59

Variant links:

Genes affected

CDH22 (HGNC:13251): (cadherin 22) This gene is a member of the cadherin superfamily. The gene product is composed of five cadherin repeat domains and a cytoplasmic tail similar to the highly conserved cytoplasmic region of classical cadherins. Expressed predominantly in the brain, this putative calcium-dependent cell adhesion protein may play an important role in morphogenesis and tissue formation in neural and non-neural cells during development and maintenance of the brain and neuroendocrine organs. [provided by RefSeq, Jul 2008]

CDH22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13353148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH22	NM_021248.3 link	c.2288C>T	p.Ser763Leu	missense_variant	Exon 12 of 12	ENST00000537909.4	NP_067071.1	Q9UJ99A8K0L9
CDH22	XM_011528994.3 link	c.2288C>T	p.Ser763Leu	missense_variant	Exon 12 of 12		XP_011527296.1	Q9UJ99
CDH22	XM_047440373.1 link	c.2048C>T	p.Ser683Leu	missense_variant	Exon 10 of 10		XP_047296329.1
CDH22	XM_024451966.2 link	c.1925C>T	p.Ser642Leu	missense_variant	Exon 12 of 12		XP_024307734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH22	ENST00000537909.4 link	c.2288C>T	p.Ser763Leu	missense_variant	Exon 12 of 12	2	NM_021248.3	ENSP00000437790.1		Q9UJ99

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000563

AC:

AN:

159772

AF XY:

0.0000684

show subpopulations

Gnomad AFR exome

AF:

0.000881

Gnomad AMR exome

AF:

0.0000380

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1405398

Hom.:

Cov.:

AF XY:

0.0000230

AC XY:

AN XY:

695712

show subpopulations

African (AFR)

AF:

0.000737

AC:

AN:

32566

American (AMR)

AF:

0.0000264

AC:

AN:

37904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25280

East Asian (EAS)

AF:

0.00

AC:

AN:

37864

South Asian (SAS)

AF:

0.00

AC:

AN:

80404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1091490

Other (OTH)

AF:

0.0000510

AC:

AN:

58770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000171

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000544

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000237

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000432

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2288C>T (p.S763L) alteration is located in exon 11 (coding exon 11) of the CDH22 gene. This alteration results from a C to T substitution at nucleotide position 2288, causing the serine (S) at amino acid position 763 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.29

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.13

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.9

M;M

PhyloP100

3.6

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.41

Sift

Benign

0.074

T;T

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

D;D

Vest4

0.31

MVP

0.75

ClinPred

0.25

GERP RS

3.8

Varity_R

0.27

gMVP

0.59

Mutation Taster

=66/34

polymorphism

(source)

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

Publications

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20-46174705-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over