Variant 20-46174841-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_021248.3(CDH22):c.2152G>C(p.Ala718Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,324,402 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A718G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 1 hom. )

Consequence

CDH22
NM_021248.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.673

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=0.06646615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH22	NM_021248.3 linkuse as main transcript	c.2152G>C	p.Ala718Pro	missense_variant	12/12	ENST00000537909.4
CDH22	XM_011528994.3 linkuse as main transcript	c.2152G>C	p.Ala718Pro	missense_variant	12/12
CDH22	XM_047440373.1 linkuse as main transcript	c.1912G>C	p.Ala638Pro	missense_variant	10/10
CDH22	XM_024451966.2 linkuse as main transcript	c.1789G>C	p.Ala597Pro	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH22	ENST00000537909.4 linkuse as main transcript	c.2152G>C	p.Ala718Pro	missense_variant	12/12	2	NM_021248.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000398

AC:

AN:

150706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000330

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:

0.000482

GnomAD4 exome

AF:

0.00000341

AC:

AN:

1173592

Hom.:

Cov.:

AF XY:

0.00000176

AC XY:

AN XY:

568882

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000410

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000398

AC:

AN:

150810

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73682

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000330

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:

0.000477

Bravo

AF:

0.000106

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

Mar 01, 2024

The c.2152G>C (p.A718P) alteration is located in exon 11 (coding exon 11) of the CDH22 gene. This alteration results from a G to C substitution at nucleotide position 2152, causing the alanine (A) at amino acid position 718 to be replaced by a proline (P). 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

0.065

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.4

DANN

Benign

0.95

DEOGEN2

Benign

0.019

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.32

.;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.066

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.94

N;N

REVEL

Benign

0.035

Sift

Benign

0.28

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.0010

B;B

Vest4

0.088

MutPred

0.38

Gain of glycosylation at A718 (P = 0.0142);Gain of glycosylation at A718 (P = 0.0142);

MVP

0.27

ClinPred

0.084

GERP RS

-0.44

Varity_R

0.19

gMVP

0.36

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