16-68834675-T-G

Position:

• chr16-68834675-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2 BA1

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.*1176T>G variant has an allele frequency of 0.04739 (4.739%, 413/8714 alleles, 12 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). 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, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10648801/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (6 hom.)
• Consequence: CDH1 NM_004360.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.754

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 -9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.*1176T>G		3_prime_UTR_variant	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.*1176T>G		3_prime_UTR_variant	15/15
CDH1	NM_001317185.2	c.*1176T>G		3_prime_UTR_variant	16/16
CDH1	NM_001317186.2	c.*1176T>G		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.*1176T>G		3_prime_UTR_variant	16/16	1	NM_004360.5	P1
CDH1	ENST00000566612.5	c.*2065T>G		3_prime_UTR_variant, NMD_transcript_variant	15/15	1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2152 AN: 152256 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00955

GnomAD4 exome AF: 0.00306 AC: 255 AN: 83228 Hom.: 6 Cov.: 0 AF XY: 0.00269 AC XY: 104 AN XY: 38604

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.00433

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000885

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.00650

GnomAD4 genome AF: 0.0142 AC: 2160 AN: 152374 Hom.: 50 Cov.: 32 AF XY: 0.0141 AC XY: 1053 AN XY: 74522

Gnomad4 AFR AF: 0.0493

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00865 Hom.: 9

Bravo AF: 0.0166

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

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

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 10, 2023

The NM_004360.5(CDH1):c.*1176T>G variant has an allele frequency of 0.04739 (4.739%, 413/8714 alleles, 12 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). 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, BP2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.73

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: rs9282654; hg19: chr16-68868578;