20-46174840-G-C

Variant names:

• chr20-46174840-G-C
• NM_021248.3:c.2153C>G

Variant summary

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

The NM_021248.3(CDH22):​c.2153C>G​(p.Ala718Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. A718P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH22 NM_021248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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=0.11458418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH22	NM_021248.3	c.2153C>G	p.Ala718Gly	missense_variant	Exon 12 of 12	ENST00000537909.4	NP_067071.1
CDH22	XM_011528994.3	c.2153C>G	p.Ala718Gly	missense_variant	Exon 12 of 12		XP_011527296.1
CDH22	XM_047440373.1	c.1913C>G	p.Ala638Gly	missense_variant	Exon 10 of 10		XP_047296329.1
CDH22	XM_024451966.2	c.1790C>G	p.Ala597Gly	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.2153C>G	p.Ala718Gly	missense_variant	Exon 12 of 12	2	NM_021248.3	ENSP00000437790.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1204514 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 586248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2153C>G (p.A718G) alteration is located in exon 11 (coding exon 11) of the CDH22 gene. This alteration results from a C to G substitution at nucleotide position 2153, causing the alanine (A) at amino acid position 718 to be replaced by a glycine (G). 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	0.054
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.32	.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.065
Sift	Benign	0.42	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0010	B;B
Vest4		0.16
MutPred		0.44		Gain of catalytic residue at S720 (P = 0.1739);Gain of catalytic residue at S720 (P = 0.1739);
MVP		0.43
ClinPred		0.18	T
GERP RS		2.1
Varity_R		0.12
gMVP		0.26

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: chr20-44803479;