18-61528163-G-C

Position:

• chr18-61528163-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_031891.4(CDH20):​c.1214G>C​(p.Gly405Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH20 NM_031891.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

CDH20 (HGNC:1760): (cadherin 20) This gene is a type II classical cadherin from the cadherin superfamily and one of three cadherin 7-like genes located in a cluster on chromosome 18. The encoded membrane protein is a calcium dependent cell-cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. Since disturbance of intracellular adhesion is a prerequisite for invasion and metastasis of tumor cells, cadherins are considered prime candidates for tumor suppressor genes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH20	NM_031891.4	c.1214G>C	p.Gly405Ala	missense_variant	7/12	ENST00000262717.9	NP_114097.2
CDH20	XM_024451165.2	c.1214G>C	p.Gly405Ala	missense_variant	7/12		XP_024306933.1
CDH20	XR_001753186.2	n.1764G>C		non_coding_transcript_exon_variant	7/11
CDH20	XR_001753187.2	n.1764G>C		non_coding_transcript_exon_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH20	ENST00000262717.9	c.1214G>C	p.Gly405Ala	missense_variant	7/12	2	NM_031891.4	ENSP00000262717.3
CDH20	ENST00000536675.2	c.1214G>C	p.Gly405Ala	missense_variant	6/11	1		ENSP00000444767.1
CDH20	ENST00000538374.5	c.1214G>C	p.Gly405Ala	missense_variant	7/12	1		ENSP00000442226.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Jun 02, 2024

The c.1214G>C (p.G405A) alteration is located in exon 6 (coding exon 6) of the CDH20 gene. This alteration results from a G to C substitution at nucleotide position 1214, causing the glycine (G) at amino acid position 405 to be replaced by an alanine (A). 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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.6	H;H;H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.050	T;T;T
Polyphen		0.95	P;P;P
Vest4		0.89
MutPred		0.79		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.68
MPC		0.88
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.82
gMVP		0.67

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: chr18-59195396;