Variant 20-46174529-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021248.3(CDH22):c.2464G>A(p.Asp822Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,516,722 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 2 hom. )

Consequence

CDH22
NM_021248.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.57

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23333713).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH22	NM_021248.3 linkuse as main transcript	c.2464G>A	p.Asp822Asn	missense_variant	12/12	ENST00000537909.4	NP_067071.1	Q9UJ99A8K0L9
CDH22	XM_011528994.3 linkuse as main transcript	c.2464G>A	p.Asp822Asn	missense_variant	12/12		XP_011527296.1	Q9UJ99
CDH22	XM_047440373.1 linkuse as main transcript	c.2224G>A	p.Asp742Asn	missense_variant	10/10		XP_047296329.1
CDH22	XM_024451966.2 linkuse as main transcript	c.2101G>A	p.Asp701Asn	missense_variant	12/12		XP_024307734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH22	ENST00000537909.4 linkuse as main transcript	c.2464G>A	p.Asp822Asn	missense_variant	12/12	2	NM_021248.3	ENSP00000437790.1		Q9UJ99

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000161

AC:

AN:

111846

Hom.:

AF XY:

0.000225

AC XY:

AN XY:

62108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000907

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:

0.000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000460

AC:

627

AN:

1364494

Hom.:

Cov.:

AF XY:

0.000452

AC XY:

304

AN XY:

672996

show subpopulations

Gnomad4 AFR exome

AF:

0.0000347

Gnomad4 AMR exome

AF:

0.000147

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:

0.000561

Gnomad4 OTH exome

AF:

0.000351

GnomAD4 genome

AF:

0.000164

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000234

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.0000817

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The c.2464G>A (p.D822N) 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 2464, causing the aspartic acid (D) at amino acid position 822 to be replaced by an asparagine (N). 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

0.084

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

0.015

Eigen_PC

Benign

0.014

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.70

.;T

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.80

P;P

Vest4

0.087

MutPred

0.48

Loss of disorder (P = 0.0837);Loss of disorder (P = 0.0837);

MVP

0.64

ClinPred

0.12

GERP RS

2.9

Varity_R

0.16

gMVP

0.35

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