rs33963999

Variant names:

• chr16-68808577-G-C
• rs33963999
• NM_004360.5:c.531+10G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-68808577-G-C
• chr16-68808577-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP2 BA1

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.531+10G>C variant has an allele frequency of 0.05787 (5.787%, 1453/25106 alleles, 39 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/CA169542/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.038 (175 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2440 hom.)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Benign reviewed by expert panel B:18
• Conservation: PhyloP100: 0.855
• Publications: 18 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 -9 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.531+10G>C		intron	N/A	NP_004351.1
	CDH1	NM_001317184.2		c.531+10G>C		intron	N/A	NP_001304113.1
	CDH1	NM_001317185.2		c.-1085+10G>C		intron	N/A	NP_001304114.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.531+10G>C		intron	N/A	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.531+10G>C		intron	N/A	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.602+10G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 5790 AN: 152172 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0580

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0385 AC: 9672 AN: 251068 AF XY: 0.0391

Gnomad AFR exome AF: 0.00910

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.0586

Gnomad NFE exome AF: 0.0546

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0538 AC: 78655 AN: 1461656 Hom.: 2440 Cov.: 33 AF XY: 0.0527 AC XY: 38312 AN XY: 727122

African (AFR) AF: 0.00833 AC: 279 AN: 33478

American (AMR) AF: 0.0237 AC: 1062 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 1035 AN: 26130

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39692

South Asian (SAS) AF: 0.0216 AC: 1867 AN: 86252

European-Finnish (FIN) AF: 0.0600 AC: 3206 AN: 53414

Middle Eastern (MID) AF: 0.0305 AC: 176 AN: 5766

European-Non Finnish (NFE) AF: 0.0612 AC: 68046 AN: 1111810

Other (OTH) AF: 0.0493 AC: 2976 AN: 60390

GnomAD4 genome AF: 0.0380 AC: 5792 AN: 152290 Hom.: 175 Cov.: 32 AF XY: 0.0381 AC XY: 2840 AN XY: 74464

African (AFR) AF: 0.0104 AC: 433 AN: 41568

American (AMR) AF: 0.0319 AC: 488 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4826

European-Finnish (FIN) AF: 0.0536 AC: 568 AN: 10606

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0581 AC: 3949 AN: 68020

Other (OTH) AF: 0.0425 AC: 90 AN: 2116

Alfa AF: 0.0492 Hom.: 49

Bravo AF: 0.0343

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hereditary diffuse gastric adenocarcinoma (4)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.55
PhyloP100		0.85
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: rs33963999; hg19: chr16-68842480; COSMIC: COSV55728473;