Genetic Variant CDH22:p.Gly708Glu (chr20-46174870-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021248.3(CDH22):c.2123G>A(p.Gly708Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,348,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CDH22
NM_021248.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.428

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0076978207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH22	NM_021248.3 link	c.2123G>A	p.Gly708Glu	missense_variant	Exon 12 of 12	ENST00000537909.4	NP_067071.1	Q9UJ99A8K0L9
CDH22	XM_011528994.3 link	c.2123G>A	p.Gly708Glu	missense_variant	Exon 12 of 12		XP_011527296.1	Q9UJ99
CDH22	XM_047440373.1 link	c.1883G>A	p.Gly628Glu	missense_variant	Exon 10 of 10		XP_047296329.1
CDH22	XM_024451966.2 link	c.1760G>A	p.Gly587Glu	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.2123G>A	p.Gly708Glu	missense_variant	Exon 12 of 12	2	NM_021248.3	ENSP00000437790.1		Q9UJ99

Frequencies

GnomAD3 genomes

AF:

0.0000795

AC:

AN:

150922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

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

GnomAD3 exomes

AF:

0.0000552

AC:

AN:

72452

Hom.:

AF XY:

0.0000236

AC XY:

AN XY:

42316

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.0000966

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000752

AC:

AN:

1197164

Hom.:

Cov.:

AF XY:

0.00000516

AC XY:

AN XY:

581586

show subpopulations

Gnomad4 AFR exome

AF:

0.000157

Gnomad4 AMR exome

AF:

0.0000506

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000306

Gnomad4 OTH exome

AF:

0.0000206

GnomAD4 genome

AF:

0.0000795

AC:

AN:

151030

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

73804

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000182

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2123G>A (p.G708E) alteration is located in exon 11 (coding exon 11) of the CDH22 gene. This alteration results from a G to A substitution at nucleotide position 2123, causing the glycine (G) at amino acid position 708 to be replaced by a glutamic acid (E). 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

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.92

DANN

Benign

0.92

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.30

.;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.097

Sift

Benign

0.16

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.20

MutPred

0.44

Loss of glycosylation at S705 (P = 0.0784);Loss of glycosylation at S705 (P = 0.0784);

MVP

0.26

ClinPred

0.022

GERP RS

-1.0

Varity_R

0.082

gMVP

0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over