rs747235838

Positions:

• chr16-68823411-T-A
• chr16-68823411-T-C

Variant summary

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

The ENST00000261769.10(CDH1):​c.1949T>A​(p.Ile650Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. I650T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 ENST00000261769.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1949T>A	p.Ile650Asn	missense_variant	13/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1766T>A	p.Ile589Asn	missense_variant	12/15		NP_001304113.1
CDH1	NM_001317185.2	c.401T>A	p.Ile134Asn	missense_variant	13/16		NP_001304114.1
CDH1	NM_001317186.2	c.-17T>A		5_prime_UTR_variant	12/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1949T>A	p.Ile650Asn	missense_variant	13/16	1	NM_004360.5	ENSP00000261769	P1
	ENST00000563916.1	n.116A>T		non_coding_transcript_exon_variant	1/3	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	0.88
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.58	D;T;.
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.9	D;.;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.88	P;.;.
Vest4		0.33
MutPred		0.77		Loss of stability (P = 0.0223);.;.;
MVP		0.73
MPC		0.88
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.76

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: chr16-68857314;