rs2229044

Variant names:

• chr16-68833484-C-T
• rs2229044
• NM_004360.5:c.2634C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-68833484-C-T
• chr16-68833484-C-A
• chr16-68833484-C-G

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.2634C>T (p.Gly878=) variant has an allele frequency of 0.03601 (3.6%, 899/24962 alleles, 20 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/CA168961/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.016 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (139 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:20
• Conservation: PhyloP100: -4.03
• 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, Labcorp Genetics (formerly Invitae), G2P, Illumina
• CDH1-related diffuse gastric and lobular breast cancer syndrome

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

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• 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: Unknown 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.2634C>T	p.Gly878Gly	synonymous	Exon 16 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.2451C>T	p.Gly817Gly	synonymous	Exon 15 of 15	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.1086C>T	p.Gly362Gly	synonymous	Exon 16 of 16	NP_001304114.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.2634C>T	p.Gly878Gly	synonymous	Exon 16 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.2451C>T	p.Gly817Gly	synonymous	Exon 15 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000562836.5	TSL:1	n.2705C>T		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2422 AN: 152036 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00595

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.00919 AC: 2311 AN: 251410 AF XY: 0.00850

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00513

Gnomad NFE exome AF: 0.00743

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.00751 AC: 10977 AN: 1461474 Hom.: 139 Cov.: 32 AF XY: 0.00741 AC XY: 5385 AN XY: 727038

African (AFR) AF: 0.0384 AC: 1285 AN: 33474

American (AMR) AF: 0.0140 AC: 627 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00968 AC: 253 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00230 AC: 198 AN: 86234

European-Finnish (FIN) AF: 0.00498 AC: 266 AN: 53410

Middle Eastern (MID) AF: 0.0930 AC: 519 AN: 5582

European-Non Finnish (NFE) AF: 0.00635 AC: 7061 AN: 1111876

Other (OTH) AF: 0.0127 AC: 765 AN: 60344

GnomAD4 genome AF: 0.0159 AC: 2424 AN: 152154 Hom.: 37 Cov.: 32 AF XY: 0.0156 AC XY: 1159 AN XY: 74388

African (AFR) AF: 0.0356 AC: 1476 AN: 41480

American (AMR) AF: 0.0159 AC: 243 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00595 AC: 63 AN: 10588

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.00690 AC: 469 AN: 68008

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0118 Hom.: 30

Bravo AF: 0.0181

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.0110

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Hereditary diffuse gastric adenocarcinoma (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	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	-0.51
CADD	Benign	5.6
DANN	Benign	0.76
PhyloP100		-4.0
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: rs2229044; hg19: chr16-68867387;