rs28372783

Variant names:

• chr16-68737219-A-C
• rs28372783
• NM_004360.5:c.-197A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-68737219-A-C
• chr16-68737219-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004360.5(CDH1):​c.-197A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 574,956 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (89 hom., cov: 33)
  • Exomes 𝑓: 0.012 (216 hom.)
• Consequence: CDH1 NM_004360.5 upstream_gene
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 16-68737219-A-C is Benign according to our data. Variant chr16-68737219-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 676637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.-197A>C		upstream_gene_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.-197A>C		upstream_gene_variant			NP_001304113.1
CDH1	NM_001317185.2	c.-1812A>C		upstream_gene_variant			NP_001304114.1
CDH1	NM_001317186.2	c.-2016A>C		upstream_gene_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.-197A>C		upstream_gene_variant		1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.-197A>C		upstream_gene_variant		1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.-197A>C		upstream_gene_variant		1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.-197A>C		upstream_gene_variant		5		ENSP00000458139.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1657 AN: 151802 Hom.: 90 Cov.: 33

Gnomad AFR AF: 0.00293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.00833

Gnomad FIN AF: 0.00265

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000707

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0120 AC: 5063 AN: 423036 Hom.: 216 Cov.: 4 AF XY: 0.0111 AC XY: 2480 AN XY: 222822

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.0708

Gnomad4 ASJ exome AF: 0.00450

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.00652

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.000683

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0109 AC: 1657 AN: 151920 Hom.: 89 Cov.: 33 AF XY: 0.0118 AC XY: 878 AN XY: 74266

Gnomad4 AFR AF: 0.00292

Gnomad4 AMR AF: 0.0464

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.00834

Gnomad4 FIN AF: 0.00265

Gnomad4 NFE AF: 0.000707

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.0166

Asia WGS AF: 0.0680 AC: 236 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.3
DANN	Benign	0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28372783; hg19: chr16-68771122;