18-61507427-G-C

Position:

• chr18-61507427-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031891.4(CDH20):​c.884G>C​(p.Arg295Thr) 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: 32)
• Consequence: CDH20 NM_031891.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.42

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH20	NM_031891.4	c.884G>C	p.Arg295Thr	missense_variant	6/12	ENST00000262717.9	NP_114097.2
CDH20	XM_024451165.2	c.884G>C	p.Arg295Thr	missense_variant	6/12		XP_024306933.1
CDH20	XR_001753186.2	n.1434G>C		non_coding_transcript_exon_variant	6/11
CDH20	XR_001753187.2	n.1434G>C		non_coding_transcript_exon_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH20	ENST00000262717.9	c.884G>C	p.Arg295Thr	missense_variant	6/12	2	NM_031891.4	ENSP00000262717.3
CDH20	ENST00000536675.2	c.884G>C	p.Arg295Thr	missense_variant	5/11	1		ENSP00000444767.1
CDH20	ENST00000538374.5	c.884G>C	p.Arg295Thr	missense_variant	6/12	1		ENSP00000442226.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 19, 2022

The c.884G>C (p.R295T) alteration is located in exon 5 (coding exon 5) of the CDH20 gene. This alteration results from a G to C substitution at nucleotide position 884, causing the arginine (R) at amino acid position 295 to be replaced by a threonine (T). 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	0.45
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.86	.;.;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.036	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.92
MutPred		0.59		Loss of methylation at R295 (P = 0.0328);Loss of methylation at R295 (P = 0.0328);Loss of methylation at R295 (P = 0.0328);
MVP		0.54
MPC		1.3
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.57
gMVP		0.68

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: chr18-59174660;