rs2010724

Variant names:

• chr16-68798511-T-C
• rs2010724
• NM_004360.5:c.164-3159T>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.164-3159T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 152,002 control chromosomes in the GnomAD database, including 15,049 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 0.42 (15049 hom., cov: 32)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290
• Publications: 11 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.164-3159T>C		intron_variant	Intron 2 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.164-3159T>C		intron_variant	Intron 2 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1452-3159T>C		intron_variant	Intron 2 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1656-3159T>C		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.164-3159T>C		intron_variant	Intron 2 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63926 AN: 151884 Hom.: 15026 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.429

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

GnomAD4 genome AF: 0.421 AC: 63994 AN: 152002 Hom.: 15049 Cov.: 32 AF XY: 0.415 AC XY: 30812 AN XY: 74304

African (AFR) AF: 0.637 AC: 26382 AN: 41440

American (AMR) AF: 0.400 AC: 6105 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1572 AN: 3468

East Asian (EAS) AF: 0.236 AC: 1219 AN: 5176

South Asian (SAS) AF: 0.300 AC: 1443 AN: 4818

European-Finnish (FIN) AF: 0.248 AC: 2621 AN: 10562

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23309 AN: 67978

Other (OTH) AF: 0.426 AC: 897 AN: 2104

Alfa AF: 0.372 Hom.: 5015

Bravo AF: 0.439

Asia WGS AF: 0.345 AC: 1201 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.66
PhyloP100		-0.29
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: rs2010724; hg19: chr16-68832414;