20-46174798-G-A

Position:

• chr20-46174798-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021248.3(CDH22):​c.2195C>T​(p.Ser732Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,341,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CDH22 NM_021248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23309025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH22	NM_021248.3	c.2195C>T	p.Ser732Leu	missense_variant	12/12	ENST00000537909.4	NP_067071.1
CDH22	XM_011528994.3	c.2195C>T	p.Ser732Leu	missense_variant	12/12		XP_011527296.1
CDH22	XM_047440373.1	c.1955C>T	p.Ser652Leu	missense_variant	10/10		XP_047296329.1
CDH22	XM_024451966.2	c.1832C>T	p.Ser611Leu	missense_variant	12/12		XP_024307734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH22	ENST00000537909.4	c.2195C>T	p.Ser732Leu	missense_variant	12/12	2	NM_021248.3	ENSP00000437790.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1341178 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 661010

Gnomad4 AFR exome AF: 0.0000362

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000333

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Apr 08, 2024

The c.2195C>T (p.S732L) alteration is located in exon 11 (coding exon 11) of the CDH22 gene. This alteration results from a C to T substitution at nucleotide position 2195, causing the serine (S) at amino acid position 732 to be replaced by a leucine (L). 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	0.086
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	0.00015
Eigen_PC	Benign	0.084
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.78	.;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.13
Sift	Benign	0.64	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.68	P;P
Vest4		0.18
MutPred		0.38		Loss of phosphorylation at S732 (P = 0.0048);Loss of phosphorylation at S732 (P = 0.0048);
MVP		0.69
ClinPred		0.72	D
GERP RS		3.5
Varity_R		0.19
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771107358; hg19: chr20-44803437; COSMIC: COSV105295836; COSMIC: COSV105295836;