rs149127230

Variant names:

• chr16-68823566-G-A
• rs149127230
• NM_004360.5:c.2104G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68823566-G-A
• chr16-68823566-G-C
• chr16-68823566-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.2104G>A (p.GLu702Lys) variant has an allele frequency of 0.001714 (0.2%, 71/41,414 alleles) in the African subpopulation of the gnomAD cohort (BA1). 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA288054/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:14
• Conservation: PhyloP100: 1.31
• Publications: 19 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

ENSG00000260798 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• 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.2104G>A	p.Glu702Lys	missense	Exon 13 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.1921G>A	p.Glu641Lys	missense	Exon 12 of 15	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.556G>A	p.Glu186Lys	missense	Exon 13 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.2104G>A	p.Glu702Lys	missense	Exon 13 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.1921G>A	p.Glu641Lys	missense	Exon 12 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000562836.5	TSL:1	n.2175G>A		non_coding_transcript_exon	Exon 12 of 15

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251084 AF XY: 0.000125

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461672 Hom.: 0 Cov.: 34 AF XY: 0.0000811 AC XY: 59 AN XY: 727120

African (AFR) AF: 0.00161 AC: 54 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5754

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1112000

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152142 Hom.: 1 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74308

African (AFR) AF: 0.00171 AC: 71 AN: 41414

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000529

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	3	Hereditary diffuse gastric adenocarcinoma (5)
-	-	4	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not specified (2)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	1	-	Endometrial carcinoma (1)
-	-	1	Familial cancer of breast;C1140680:Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.60
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.060
Sift	Benign	0.52	T
Sift4G	Benign	0.41	T
Polyphen		0.014	B
Vest4		0.24
MVP		0.69
MPC		0.31
ClinPred		0.014	T
GERP RS		1.5
Varity_R		0.074
gMVP		0.53
Mutation Taster		=84/16	polymorphism

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: rs149127230; hg19: chr16-68857469; COSMIC: COSV55744367; COSMIC: COSV55744367;