18-61502956-T-C

Position:

• chr18-61502956-T-C

Variant summary

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

The NM_031891.4(CDH20):​c.665T>C​(p.Val222Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,447,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH20 NM_031891.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3380605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH20	NM_031891.4	c.665T>C	p.Val222Ala	missense_variant	5/12	ENST00000262717.9	NP_114097.2
CDH20	XM_024451165.2	c.665T>C	p.Val222Ala	missense_variant	5/12		XP_024306933.1
CDH20	XR_001753186.2	n.1215T>C		non_coding_transcript_exon_variant	5/11
CDH20	XR_001753187.2	n.1215T>C		non_coding_transcript_exon_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH20	ENST00000262717.9	c.665T>C	p.Val222Ala	missense_variant	5/12	2	NM_031891.4	ENSP00000262717.3
CDH20	ENST00000536675.2	c.665T>C	p.Val222Ala	missense_variant	4/11	1		ENSP00000444767.1
CDH20	ENST00000538374.5	c.665T>C	p.Val222Ala	missense_variant	5/12	1		ENSP00000442226.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447008 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719448

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: 9.03e-7

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

Oct 21, 2021

The c.665T>C (p.V222A) alteration is located in exon 4 (coding exon 4) of the CDH20 gene. This alteration results from a T to C substitution at nucleotide position 665, causing the valine (V) at amino acid position 222 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	Benign	0.19
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.063
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.27	B;B;B
Vest4		0.36
MutPred		0.44		Gain of ubiquitination at K219 (P = 0.0509);Gain of ubiquitination at K219 (P = 0.0509);Gain of ubiquitination at K219 (P = 0.0509);
MVP		0.33
MPC		0.44
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.59
gMVP		0.27

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: rs199772820; hg19: chr18-59170189;