Genetic Variant NM_004360.5:c.1680G>C (chr16-68819394-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004360.5(CDH1):c.1680G>C(p.Thr560Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,613,740 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T560T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 26 hom. )

Consequence

CDH1
NM_004360.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29

Conservation

PhyloP100: -3.61

Publications

9 publications found

Variant links:

COSMIC-nc: COSV55731541

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

CDH1 links:

ENSG00000260798 (HGNC:):

ENSG00000260798 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 16-68819394-G-C is Benign according to our data. Variant chr16-68819394-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.61 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00261 (398/152234) while in subpopulation SAS AF = 0.00519 (25/4816). AF 95% confidence interval is 0.00361. There are 0 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 398 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH1	NM_004360.5	MANE Select	c.1680G>C	p.Thr560Thr	synonymous	Exon 11 of 16	NP_004351.1	A0A0U2ZQU7
CDH1	NM_001317184.2		c.1497G>C	p.Thr499Thr	synonymous	Exon 10 of 15	NP_001304113.1	P12830-2
CDH1	NM_001317185.2		c.132G>C	p.Thr44Thr	synonymous	Exon 11 of 16	NP_001304114.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1680G>C	p.Thr560Thr	synonymous	Exon 11 of 16	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6	TSL:1	c.1497G>C	p.Thr499Thr	synonymous	Exon 10 of 15	ENSP00000414946.2	P12830-2
CDH1	ENST00000562836.5	TSL:1	n.1751G>C		non_coding_transcript_exon	Exon 10 of 15

Frequencies

GnomAD3 genomes

AF:

0.00262

AC:

398

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00398

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00337

AC:

848

AN:

251482

AF XY:

0.00386

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.00449

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00352

AC:

5151

AN:

1461506

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

2662

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33470

American (AMR)

AF:

0.00114

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00698

AC:

602

AN:

86242

European-Finnish (FIN)

AF:

0.00240

AC:

128

AN:

53420

Middle Eastern (MID)

AF:

0.00146

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

0.00373

AC:

4145

AN:

1111984

Other (OTH)

AF:

0.00283

AC:

171

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

301

602

903

1204

1505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00261

AC:

398

AN:

152234

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41534

American (AMR)

AF:

0.00301

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00519

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00398

AC:

271

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00272

Hom.:

Bravo

AF:

0.00223

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00393

EpiControl

AF:

0.00474

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

Hereditary diffuse gastric adenocarcinoma (7)

not specified (7)

Hereditary cancer-predisposing syndrome (4)

Breast and/or ovarian cancer (1)

Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.0040

(source)

DANN

Benign

0.62

PhyloP100

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over