rs3743674

chr16-68737469-C-T

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.48+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 1,537,000 control chromosomes in the GnomAD database, including 572,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.80 (50036 hom., cov: 35)
  • Exomes 𝑓: 0.87 (522253 hom.)
• Consequence: CDH1 NM_004360.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001643
• Clinical Significance: Benign reviewed by expert panel U:1 B:20
• Conservation: PhyloP100: -0.132

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=-0.79).
• BP6: Variant 16-68737469-C-T is Benign according to our data. Variant chr16-68737469-C-T is described in ClinVar as [Benign]. Clinvar id is 136692.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68737469-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.48+6C>T		splice_donor_region_variant, intron_variant		ENST00000261769.10
CDH1	NM_001317184.2	c.48+6C>T		splice_donor_region_variant, intron_variant
CDH1	NM_001317185.2	c.-1568+6C>T		splice_donor_region_variant, intron_variant
CDH1	NM_001317186.2	c.-1772+6C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.48+6C>T		splice_donor_region_variant, intron_variant		1	NM_004360.5	P1
CDH1	ENST00000422392.6	c.48+6C>T		splice_donor_region_variant, intron_variant		1
CDH1	ENST00000566612.5	c.48+6C>T		splice_donor_region_variant, intron_variant, NMD_transcript_variant		1
CDH1	ENST00000566510.5	c.48+6C>T		splice_donor_region_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.805 AC: 122401 AN: 152054 Hom.: 50031 Cov.: 35

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.930

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.850

Gnomad NFE AF: 0.884

Gnomad OTH AF: 0.831

GnomAD3 exomes AF: 0.816 AC: 108886 AN: 133422 Hom.: 44928 AF XY: 0.820 AC XY: 60266 AN XY: 73462

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.741

Gnomad ASJ exome AF: 0.928

Gnomad EAS exome AF: 0.765

Gnomad SAS exome AF: 0.778

Gnomad FIN exome AF: 0.827

Gnomad NFE exome AF: 0.878

Gnomad OTH exome AF: 0.857

GnomAD4 exome AF: 0.867 AC: 1200027 AN: 1384830 Hom.: 522253 Cov.: 45 AF XY: 0.865 AC XY: 591464 AN XY: 684018

Gnomad4 AFR exome AF: 0.652

Gnomad4 AMR exome AF: 0.756

Gnomad4 ASJ exome AF: 0.929

Gnomad4 EAS exome AF: 0.765

Gnomad4 SAS exome AF: 0.778

Gnomad4 FIN exome AF: 0.837

Gnomad4 NFE exome AF: 0.886

Gnomad4 OTH exome AF: 0.858

GnomAD4 genome AF: 0.805 AC: 122443 AN: 152170 Hom.: 50036 Cov.: 35 AF XY: 0.800 AC XY: 59502 AN XY: 74384

Gnomad4 AFR AF: 0.663

Gnomad4 AMR AF: 0.799

Gnomad4 ASJ AF: 0.930

Gnomad4 EAS AF: 0.773

Gnomad4 SAS AF: 0.784

Gnomad4 FIN AF: 0.825

Gnomad4 NFE AF: 0.884

Gnomad4 OTH AF: 0.828

Alfa AF: 0.853 Hom.: 10658

Bravo AF: 0.796

Asia WGS AF: 0.774 AC: 2692 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:20

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary diffuse gastric adenocarcinoma Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Malignant tumor of prostate Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -

Blepharocheilodontic syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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.48+6C>T variant has an allele frequency of 0.81161 (81%, 129,383/159,416 alleles) in the gnomAD cohort (BA1). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.2
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.032
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: rs3743674; hg19: chr16-68771372; COSMIC: COSV55733220;