rs1078621

Variant names:

• chr16-68745093-G-A
• rs1078621
• NM_004360.5:c.163+6682G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68745093-G-A
• chr16-68745093-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004360.5(CDH1):​c.163+6682G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 151,620 control chromosomes in the GnomAD database, including 19,078 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 0.48 (19078 hom., cov: 29)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 17 publications found

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]

CDH1 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000309644 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.163+6682G>A		intron_variant	Intron 2 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.163+6682G>A		intron_variant	Intron 2 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1453+6682G>A		intron_variant	Intron 2 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1657+6682G>A		intron_variant	Intron 2 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.163+6682G>A		intron_variant	Intron 2 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73453 AN: 151502 Hom.: 19080 Cov.: 29

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.485 AC: 73470 AN: 151620 Hom.: 19078 Cov.: 29 AF XY: 0.484 AC XY: 35840 AN XY: 74034

African (AFR) AF: 0.285 AC: 11776 AN: 41368

American (AMR) AF: 0.474 AC: 7194 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1800 AN: 3468

East Asian (EAS) AF: 0.490 AC: 2507 AN: 5112

South Asian (SAS) AF: 0.537 AC: 2584 AN: 4808

European-Finnish (FIN) AF: 0.578 AC: 6055 AN: 10470

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.585 AC: 39738 AN: 67904

Other (OTH) AF: 0.508 AC: 1071 AN: 2108

Alfa AF: 0.547 Hom.: 17023

Bravo AF: 0.467

Asia WGS AF: 0.471 AC: 1640 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.2
DANN	Benign	0.62
PhyloP100		-0.030
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1078621; hg19: chr16-68778996; COSMIC: COSV55741854; COSMIC: COSV55741854;