Genetic Variant NM_021248.3:c.2104G>T (chr20-46174889-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_021248.3(CDH22):c.2104G>T(p.Gly702Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000792 in 1,263,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G702R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

CDH22
NM_021248.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.238

Publications

0 publications found

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3466377).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021248.3. 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
	CDH22	NM_021248.3	MANE Select	c.2104G>T	p.Gly702Trp	missense	Exon 12 of 12	NP_067071.1	Q9UJ99

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH22	ENST00000537909.4	TSL:2 MANE Select	c.2104G>T	p.Gly702Trp	missense	Exon 12 of 12	ENSP00000437790.1	Q9UJ99
CDH22	ENST00000946368.1		c.2104G>T	p.Gly702Trp	missense	Exon 12 of 12	ENSP00000616427.1
CDH22	ENST00000946370.1		c.2104G>T	p.Gly702Trp	missense	Exon 12 of 12	ENSP00000616429.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.92e-7

AC:

AN:

1263412

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

619562

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27592

American (AMR)

AF:

0.00

AC:

AN:

30162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21734

East Asian (EAS)

AF:

0.00

AC:

AN:

30418

South Asian (SAS)

AF:

0.0000184

AC:

AN:

54336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1013130

Other (OTH)

AF:

0.00

AC:

AN:

51156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.0037

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

-0.016

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.44

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.5

PhyloP100

0.24

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

REVEL

Benign

0.23

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.018

Polyphen

0.91

Vest4

0.35

MutPred

0.48

Loss of relative solvent accessibility (P = 0.0676)

MVP

0.50

ClinPred

0.72

GERP RS

2.9

Varity_R

0.096

gMVP

0.49

Mutation Taster

=77/23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over