rs9941051

Variant names:

• chr16-68761471-C-T
• rs9941051
• NM_004360.5:c.163+23060C>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+23060C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.867 in 152,276 control chromosomes in the GnomAD database, including 57,367 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 0.87 (57367 hom., cov: 33)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.671
• Publications: 12 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.163+23060C>T		intron_variant	Intron 2 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.163+23060C>T		intron_variant	Intron 2 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1453+23060C>T		intron_variant	Intron 2 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1657+23060C>T		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+23060C>T		intron_variant	Intron 2 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131905 AN: 152158 Hom.: 57339 Cov.: 33

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.876

Gnomad NFE AF: 0.889

Gnomad OTH AF: 0.876

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

GnomAD4 genome AF: 0.867 AC: 131987 AN: 152276 Hom.: 57367 Cov.: 33 AF XY: 0.861 AC XY: 64073 AN XY: 74446

African (AFR) AF: 0.871 AC: 36175 AN: 41546

American (AMR) AF: 0.823 AC: 12596 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3227 AN: 3472

East Asian (EAS) AF: 0.775 AC: 4016 AN: 5182

South Asian (SAS) AF: 0.784 AC: 3778 AN: 4818

European-Finnish (FIN) AF: 0.825 AC: 8760 AN: 10616

Middle Eastern (MID) AF: 0.870 AC: 254 AN: 292

European-Non Finnish (NFE) AF: 0.889 AC: 60494 AN: 68026

Other (OTH) AF: 0.872 AC: 1844 AN: 2114

Alfa AF: 0.870 Hom.: 11524

Bravo AF: 0.866

Asia WGS AF: 0.796 AC: 2771 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.47
DANN	Benign	0.79
PhyloP100		-0.67
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: rs9941051; hg19: chr16-68795374;