18-65762858-G-T

Variant names:

• chr18-65762858-G-T
• rs1916235036
• NM_004361.5:c.16G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004361.5(CDH7):​c.16G>T​(p.Val6Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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)
• Consequence: CDH7 NM_004361.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67
• Publications: 0 publications found

Genes affected

CDH7 (HGNC:1766): (cadherin 7) This gene encodes a type II classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium dependent cell-cell adhesion molecule is 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 histidine-alanine-valine (HAV) cell adhesion recognition sequence specific to type I cadherins. Cadherins mediate cell-cell binding in a homophilic manner, contributing to the sorting of heterogeneous cell types. Mutations in this gene may be associated with bipolar disease in human patients. This gene is present in a gene cluster on chromosome 18. [provided by RefSeq, May 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14030972).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH7	NM_004361.5	c.16G>T	p.Val6Leu	missense_variant	Exon 2 of 12	ENST00000397968.4	NP_004352.2
CDH7	NM_001362438.2	c.16G>T	p.Val6Leu	missense_variant	Exon 2 of 12		NP_001349367.1
CDH7	NM_033646.4	c.16G>T	p.Val6Leu	missense_variant	Exon 2 of 12		NP_387450.1
CDH7	NM_001317214.3	c.16G>T	p.Val6Leu	missense_variant	Exon 2 of 11		NP_001304143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH7	ENST00000397968.4	c.16G>T	p.Val6Leu	missense_variant	Exon 2 of 12	1	NM_004361.5	ENSP00000381058.2
CDH7	ENST00000323011.7	c.16G>T	p.Val6Leu	missense_variant	Exon 2 of 12	1		ENSP00000319166.3
CDH7	ENST00000536984.6	c.16G>T	p.Val6Leu	missense_variant	Exon 2 of 11	1		ENSP00000443030.2
CDH7	ENST00000581601.1	n.-150G>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>T (p.V6L) alteration is located in exon 2 (coding exon 1) of the CDH7 gene. This alteration results from a G to T substitution at nucleotide position 16, causing the valine (V) at amino acid position 6 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	0.11
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	-0.062
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;.;N
PhyloP100		5.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.13	N;N;N
REVEL	Benign	0.071
Sift	Benign	0.51	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.043	B;B;B
Vest4		0.37
MutPred		0.39		Loss of methylation at K5 (P = 0.0346);Loss of methylation at K5 (P = 0.0346);Loss of methylation at K5 (P = 0.0346);
MVP		0.43
MPC		0.34
ClinPred		0.72	D
GERP RS		5.8
Varity_R		0.13
gMVP		0.74

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

Other links and lift over

dbSNP: rs1916235036; hg19: chr18-63430094;