rs189334685

chr16-68822137-T-Achr16-68822137-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004360.5(CDH1):c.1848T>A(p.Asp616Glu) 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. Synonymous variant affecting the same amino acid position (i.e. D616D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1848T>A	p.Asp616Glu	missense_variant	12/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1665T>A	p.Asp555Glu	missense_variant	11/15
CDH1	NM_001317185.2	c.300T>A	p.Asp100Glu	missense_variant	12/16
CDH1	NM_001317186.2	c.-118T>A		5_prime_UTR_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1848T>A	p.Asp616Glu	missense_variant	12/16	1	NM_004360.5	P1
	ENST00000563916.1	n.263+1127A>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;T;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
MutationTaster	Benign	0.91	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;.;.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.91	P;.;.;.
Vest4		0.89
MutPred		0.92		Gain of glycosylation at P621 (P = 0.1315);.;Gain of glycosylation at P621 (P = 0.1315);.;
MVP		0.83
MPC		0.65
ClinPred		0.98	D
GERP RS		-7.4
Varity_R		0.91
gMVP		0.83

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: chr16-68856040;