20-46174631-G-T

Variant names:

• chr20-46174631-G-T
• rs747323649
• NM_021248.3:c.2362C>A

Variant summary

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

The NM_021248.3(CDH22):​c.2362C>A​(p.Leu788Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,550,384 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. L788P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (1 hom.)
• Consequence: CDH22 NM_021248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.908

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=0.32431382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH22	NM_021248.3	c.2362C>A	p.Leu788Met	missense_variant	Exon 12 of 12	ENST00000537909.4	NP_067071.1
CDH22	XM_011528994.3	c.2362C>A	p.Leu788Met	missense_variant	Exon 12 of 12		XP_011527296.1
CDH22	XM_047440373.1	c.2122C>A	p.Leu708Met	missense_variant	Exon 10 of 10		XP_047296329.1
CDH22	XM_024451966.2	c.1999C>A	p.Leu667Met	missense_variant	Exon 12 of 12		XP_024307734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH22	ENST00000537909.4	c.2362C>A	p.Leu788Met	missense_variant	Exon 12 of 12	2	NM_021248.3	ENSP00000437790.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152220 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: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 19 AN: 149184 Hom.: 0 AF XY: 0.000196 AC XY: 16 AN XY: 81662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000787

Gnomad SAS exome AF: 0.000689

Gnomad FIN exome AF: 0.000133

Gnomad NFE exome AF: 0.0000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000601 AC: 84 AN: 1398056 Hom.: 1 Cov.: 30 AF XY: 0.0000868 AC XY: 60 AN XY: 691040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.000914

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000276

Gnomad4 OTH exome AF: 0.0000514

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000893 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2362C>A (p.L788M) alteration is located in exon 11 (coding exon 11) of the CDH22 gene. This alteration results from a C to A substitution at nucleotide position 2362, causing the leucine (L) at amino acid position 788 to be replaced by a methionine (M). 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	0.23
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.91	.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.97	D;D
Vest4		0.24
MutPred		0.73		Loss of stability (P = 0.0505);Loss of stability (P = 0.0505);
MVP		0.81
ClinPred		0.30	T
GERP RS		1.7
Varity_R		0.54
gMVP		0.42

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

Other links and lift over

dbSNP: rs747323649; hg19: chr20-44803270;