16-68808753-G-A

Position:

• chr16-68808753-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4 BS2_Supporting

The NM_004360.5(CDH1):​c.592G>A​(p.Asp198Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.48

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]

CDH1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a domain Cadherin 1 (size 107) in uniprot entity CADH1_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_004360.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.37950987).
• BS2: High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.592G>A	p.Asp198Asn	missense_variant	5/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.592G>A	p.Asp198Asn	missense_variant	5/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1024G>A		5_prime_UTR_variant	5/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1228G>A		5_prime_UTR_variant	5/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.592G>A	p.Asp198Asn	missense_variant	5/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251246 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 2023	The p.D198N variant (also known as c.592G>A), located in coding exon 5 of the CDH1 gene, results from a G to A substitution at nucleotide position 592. The aspartic acid at codon 198 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Benign	0.85
DEOGEN2	Uncertain	0.51	D;T;T;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.3	M;.;.;.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.5	D;.;.;.;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.019	D;.;.;.;D
Sift4G	Uncertain	0.040	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.31
MutPred		0.57		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.86
MPC		0.89
ClinPred		0.58	D
GERP RS		5.8
Varity_R		0.60
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs1308439785; hg19: chr16-68842656;