NM_004360.5:c.2295+440A>C

Variant names:

• chr16-68828744-A-C
• rs3785078
• NM_004360.5:c.2295+440A>C

Variant summary

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

The NM_004360.5(CDH1):​c.2295+440A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 152,246 control chromosomes in the GnomAD database, including 924 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 0.10 (924 hom., cov: 32)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 6 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2295+440A>C		intron_variant	Intron 14 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2112+440A>C		intron_variant	Intron 13 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.747+440A>C		intron_variant	Intron 14 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.330+440A>C		intron_variant	Intron 13 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2295+440A>C		intron_variant	Intron 14 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15385 AN: 152128 Hom.: 927 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0580

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.0979

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

GnomAD4 genome AF: 0.101 AC: 15388 AN: 152246 Hom.: 924 Cov.: 32 AF XY: 0.102 AC XY: 7569 AN XY: 74424

African (AFR) AF: 0.0262 AC: 1089 AN: 41558

American (AMR) AF: 0.126 AC: 1920 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 506 AN: 3472

East Asian (EAS) AF: 0.116 AC: 601 AN: 5190

South Asian (SAS) AF: 0.0581 AC: 280 AN: 4822

European-Finnish (FIN) AF: 0.153 AC: 1616 AN: 10586

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9068 AN: 68008

Other (OTH) AF: 0.0974 AC: 206 AN: 2116

Alfa AF: 0.120 Hom.: 1471

Bravo AF: 0.0974

Asia WGS AF: 0.0660 AC: 230 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.60
PhyloP100		1.7
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: rs3785078; hg19: chr16-68862647;