rs114885938

Positions:

• chr16-68815710-A-C
• chr16-68815710-A-G
• chr16-68815710-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004360.5(CDH1):​c.1516A>C​(p.Thr506Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T506A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.476

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a 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 protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1516A>C	p.Thr506Pro	missense_variant	10/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1333A>C	p.Thr445Pro	missense_variant	9/15
CDH1	NM_001317185.2	c.-33A>C		5_prime_UTR_variant	10/16
CDH1	NM_001317186.2	c.-304A>C		5_prime_UTR_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1516A>C	p.Thr506Pro	missense_variant	10/16	1	NM_004360.5	P1
	ENST00000563916.1	n.264-51T>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.075
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.84	T;D;T;D;T
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.
MutationTaster	Benign	0.76	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.7	D;.;.;.;D
REVEL	Benign	0.25
Sift	Uncertain	0.017	D;.;.;.;D
Sift4G	Benign	0.087	T;T;T;T;T
Polyphen		0.87	P;.;.;.;.
Vest4		0.69
MutPred		0.61		Loss of glycosylation at T506 (P = 0.0342);Loss of glycosylation at T506 (P = 0.0342);.;Loss of glycosylation at T506 (P = 0.0342);.;
MVP		0.83
MPC		0.88
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.52
gMVP		0.80

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: chr16-68849613;