chr16-68813336-C-G

Variant names:

• chr16-68813336-C-G
• NM_004360.5:c.1161C>G

Variant summary

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

The NM_004360.5(CDH1):​c.1161C>G​(p.Asn387Lys) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N387N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.16

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]

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, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1161C>G	p.Asn387Lys	missense_variant	Exon 9 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317185.2	c.-455C>G		5_prime_UTR_variant	Exon 9 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-659C>G		5_prime_UTR_variant	Exon 9 of 15		NP_001304115.1
CDH1	NM_001317184.2	c.1137+1073C>G		intron_variant	Intron 8 of 14		NP_001304113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1161C>G	p.Asn387Lys	missense_variant	Exon 9 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 24, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	1.5
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;T;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	4.0	H;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.5	D;.;.;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.84
MutPred		0.61		Gain of ubiquitination at N387 (P = 0.0109);Gain of ubiquitination at N387 (P = 0.0109);Gain of ubiquitination at N387 (P = 0.0109);Gain of ubiquitination at N387 (P = 0.0109);
MVP		0.80
MPC		0.96
ClinPred		1.0	D
GERP RS		-5.0
Varity_R		0.91
gMVP		0.81

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: chr16-68847239;