20-46174772-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021248.3(CDH22):c.2221G>C(p.Glu741Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: CDH22 NM_021248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31129363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH22	NM_021248.3	c.2221G>C	p.Glu741Gln	missense_variant	12/12	ENST00000537909.4
CDH22	XM_011528994.3	c.2221G>C	p.Glu741Gln	missense_variant	12/12
CDH22	XM_047440373.1	c.1981G>C	p.Glu661Gln	missense_variant	10/10
CDH22	XM_024451966.2	c.1858G>C	p.Glu620Gln	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH22	ENST00000537909.4	c.2221G>C	p.Glu741Gln	missense_variant	12/12	2	NM_021248.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.2221G>C (p.E741Q) 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 2221, causing the glutamic acid (E) at amino acid position 741 to be replaced by a glutamine (Q). 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	0.082
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	0.023
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.51	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.99	L;L
MutationTaster	Benign	0.81	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.17
Sift	Benign	0.57	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.91	P;P
Vest4		0.080
MutPred		0.41		Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);
MVP		0.72
ClinPred		0.61	D
GERP RS		2.8
Varity_R		0.21
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-44803411;