16-68829819-C-T

Position:

• chr16-68829819-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.2439+22C>T has a frequency of 0.00096 in gnomAD (271 of 280,840), with a maximum subpopulation frequency of 0.01029 (255 of 24,778) in the African population and includes one homozygote (BA1; http://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in the literature. In summary, this variant meets criteria to be classified as benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8130277/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.0033 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -0.0920

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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2439+22C>T		intron_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2256+22C>T		intron_variant			NP_001304113.1
CDH1	NM_001317185.2	c.891+22C>T		intron_variant			NP_001304114.1
CDH1	NM_001317186.2	c.474+22C>T		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2439+22C>T		intron_variant		1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 486 AN: 152106 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000726 AC: 181 AN: 249472 Hom.: 0 AF XY: 0.000518 AC XY: 70 AN XY: 135014

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000341 AC: 498 AN: 1459388 Hom.: 3 Cov.: 31 AF XY: 0.000313 AC XY: 227 AN XY: 726196

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000746

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152222 Hom.: 5 Cov.: 32 AF XY: 0.00339 AC XY: 252 AN XY: 74418

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00351

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Malignant tumor of prostate Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 08, 2023

The c.2439+22C>T has a frequency of 0.00096 in gnomAD (271 of 280,840), with a maximum subpopulation frequency of 0.01029 (255 of 24,778) in the African population and includes one homozygote (BA1; http://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in the literature. In summary, this variant meets criteria to be classified as benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.8
DANN	Benign	0.54

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: rs34751606; hg19: chr16-68863722;