5-31316243-A-G

Position:

• chr5-31316243-A-G

Variant summary

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

The NM_004932.4(CDH6):​c.1426A>G​(p.Ile476Val) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH6 NM_004932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10

Genes affected

CDH6 (HGNC:1765): (cadherin 6) This gene encodes a member of the cadherin superfamily. Cadherins are membrane glycoproteins that mediate homophilic cell-cell adhesion and play critical roles in cell differentiation and morphogenesis. The encoded protein is a type II cadherin and may play a role in kidney development as well as endometrium and placenta formation. Decreased expression of this gene may be associated with tumor growth and metastasis. [provided by RefSeq, May 2011]

CDH6 (HGNC:):

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=0.26377067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH6	NM_004932.4	c.1426A>G	p.Ile476Val	missense_variant	9/12	ENST00000265071.3	NP_004923.1
CDH6	NM_001362435.2	c.1426A>G	p.Ile476Val	missense_variant	9/11		NP_001349364.1
CDH6	XM_011513921.4	c.1426A>G	p.Ile476Val	missense_variant	9/12		XP_011512223.1
CDH6	XM_047416591.1	c.1426A>G	p.Ile476Val	missense_variant	9/12		XP_047272547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH6	ENST00000265071.3	c.1426A>G	p.Ile476Val	missense_variant	9/12	2	NM_004932.4	ENSP00000265071.2
CDH6	ENST00000514738.5	c.1261A>G	p.Ile421Val	missense_variant	9/11	1		ENSP00000424843.1
CDH6	ENST00000504835.1	n.-7A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 24, 2024

The c.1426A>G (p.I476V) alteration is located in exon 9 (coding exon 8) of the CDH6 gene. This alteration results from a A to G substitution at nucleotide position 1426, causing the isoleucine (I) at amino acid position 476 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.0020
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.78	.;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.084
Sift	Benign	0.26	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.023	.;B
Vest4		0.41
MutPred		0.48		.;Loss of ubiquitination at K477 (P = 0.1278);
MVP		0.43
MPC		0.44
ClinPred		0.74	D
GERP RS		3.9
Varity_R		0.046
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs995046641; hg19: chr5-31316350;