rs12599393

chr16-68795118-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004360.5(CDH1):c.164-6552C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 152,032 control chromosomes in the GnomAD database, including 5,558 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (5558 hom., cov: 31)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.164-6552C>T		intron_variant		ENST00000261769.10
CDH1	NM_001317184.2	c.164-6552C>T		intron_variant
CDH1	NM_001317185.2	c.-1452-6552C>T		intron_variant
CDH1	NM_001317186.2	c.-1656-6552C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.164-6552C>T		intron_variant		1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40491 AN: 151914 Hom.: 5561 Cov.: 31

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.290

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.266 AC: 40494 AN: 152032 Hom.: 5558 Cov.: 31 AF XY: 0.264 AC XY: 19625 AN XY: 74302

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.398

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.287

Alfa AF: 0.299 Hom.: 11840

Bravo AF: 0.263

Asia WGS AF: 0.243 AC: 847 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.3
Dann	Benign	0.63

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: rs12599393; hg19: chr16-68829021; COSMIC: COSV55728744;