5-31317411-C-T

Variant summary

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

The NM_004932.4(CDH6):c.1549C>T(p.Pro517Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH6 NM_004932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

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]

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=0.12695986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH6	NM_004932.4	c.1549C>T	p.Pro517Ser	missense_variant	10/12	ENST00000265071.3
CDH6	NM_001362435.2	c.1549C>T	p.Pro517Ser	missense_variant	10/11
CDH6	XM_011513921.4	c.1549C>T	p.Pro517Ser	missense_variant	10/12
CDH6	XM_047416591.1	c.1549C>T	p.Pro517Ser	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH6	ENST00000265071.3	c.1549C>T	p.Pro517Ser	missense_variant	10/12	2	NM_004932.4	P1
CDH6	ENST00000514738.5	c.1384C>T	p.Pro462Ser	missense_variant	10/11	1
CDH6	ENST00000504835.1	n.117C>T		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Mar 22, 2023

The c.1549C>T (p.P517S) alteration is located in exon 10 (coding exon 9) of the CDH6 gene. This alteration results from a C to T substitution at nucleotide position 1549, causing the proline (P) at amino acid position 517 to be replaced by a serine (S). 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	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	0.0039
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Benign	0.096
Sift	Benign	0.27	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.051	.;B
Vest4		0.096
MutPred		0.36		.;Loss of methylation at K514 (P = 0.0696);
MVP		0.42
MPC		0.53
ClinPred		0.92	D
GERP RS		4.8
Varity_R		0.50
gMVP		0.41

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: chr5-31317518;