NM_021248.3:c.2206G>A

Variant names:

• chr20-46174787-C-T
• rs749350713
• NM_021248.3:c.2206G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021248.3(CDH22):​c.2206G>A​(p.Gly736Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000866 in 1,500,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CDH22 NM_021248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42
• 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=0.31189835).

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.2206G>A	p.Gly736Arg	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.2206G>A	p.Gly736Arg	missense	Exon 12 of 12	ENSP00000437790.1	Q9UJ99
	CDH22	ENST00000946368.1		c.2206G>A	p.Gly736Arg	missense	Exon 12 of 12	ENSP00000616427.1
	CDH22	ENST00000946370.1		c.2206G>A	p.Gly736Arg	missense	Exon 12 of 12	ENSP00000616429.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151624 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 2 AN: 98930 AF XY: 0.0000358

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 12 AN: 1348968 Hom.: 0 Cov.: 30 AF XY: 0.00000601 AC XY: 4 AN XY: 665424

African (AFR) AF: 0.00 AC: 0 AN: 28000

American (AMR) AF: 0.00 AC: 0 AN: 31580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24032

East Asian (EAS) AF: 0.00 AC: 0 AN: 30778

South Asian (SAS) AF: 0.00 AC: 0 AN: 75364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 0.00000752 AC: 8 AN: 1063734

Other (OTH) AF: 0.0000709 AC: 4 AN: 56446

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151624 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74042

African (AFR) AF: 0.00 AC: 0 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67812

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

ExAC AF: 0.0000288 AC: 3

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	0.19
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.00026
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.065	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.21
Sift	Benign	0.47	T
Sift4G	Benign	0.79	T
Polyphen		1.0	D
Vest4		0.055
MutPred		0.35		Gain of glycosylation at P734 (P = 0.1304)
MVP		0.64
ClinPred		0.82	D
GERP RS		3.8
Varity_R		0.13
gMVP		0.47
Mutation Taster		=88/12	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

dbSNP: rs749350713; hg19: chr20-44803426;