20-46174772-C-G

Variant names:

• chr20-46174772-C-G
• NM_021248.3:c.2221G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 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
• Publications: 0 publications found

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

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=0.31129363).

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.2221G>C	p.Glu741Gln	missense	Exon 12 of 12	NP_067071.1	Q9UJ99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH22	ENST00000537909.4	TSL:2 MANE Select	c.2221G>C	p.Glu741Gln	missense	Exon 12 of 12	ENSP00000437790.1	Q9UJ99
	CDH22	ENST00000946368.1		c.2221G>C	p.Glu741Gln	missense	Exon 12 of 12	ENSP00000616427.1
	CDH22	ENST00000946370.1		c.2221G>C	p.Glu741Gln	missense	Exon 12 of 12	ENSP00000616429.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.023
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.99	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.17
Sift	Benign	0.57	T
Sift4G	Benign	0.53	T
Polyphen		0.91	P
Vest4		0.080
MutPred		0.41		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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

hg19: chr20-44803411;