20-46174870-C-T

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

1
18

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]

Genome browser will be placed here

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
CDH22NM_021248.3 linkc.2123G>A p.Gly708Glu missense_variant Exon 12 of 12 ENST00000537909.4 NP_067071.1 Q9UJ99A8K0L9
CDH22XM_011528994.3 linkc.2123G>A p.Gly708Glu missense_variant Exon 12 of 12 XP_011527296.1 Q9UJ99
CDH22XM_047440373.1 linkc.1883G>A p.Gly628Glu missense_variant Exon 10 of 10 XP_047296329.1
CDH22XM_024451966.2 linkc.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
CDH22ENST00000537909.4 linkc.2123G>A p.Gly708Glu missense_variant Exon 12 of 12 2 NM_021248.3 ENSP00000437790.1 Q9UJ99

Frequencies

GnomAD3 genomes
AF:
0.0000795
AC:
12
AN:
150922
Hom.:
0
Cov.:
31
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:
4
AN:
72452
Hom.:
0
AF XY:
0.0000236
AC XY:
1
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:
9
AN:
1197164
Hom.:
0
Cov.:
37
AF XY:
0.00000516
AC XY:
3
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:
12
AN:
151030
Hom.:
0
Cov.:
31
AF XY:
0.000122
AC XY:
9
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.:
0
Bravo
AF:
0.0000945
ExAC
AF:
0.0000182
AC:
2

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
T
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
N
LIST_S2
Benign
0.30
.;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.0077
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;L
PrimateAI
Pathogenic
0.80
T
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
T
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.

Other links and lift over

dbSNP: rs553040712; hg19: chr20-44803509; API