16-68737430-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004360.5(CDH1):c.15C>G(p.Ser5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S5N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.932

Publications

1 publications found

Variant links:

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

CDH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14161658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH1	NM_004360.5 link	c.15C>G	p.Ser5Arg	missense_variant	Exon 1 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 link	c.15C>G	p.Ser5Arg	missense_variant	Exon 1 of 15		NP_001304113.1
CDH1	NM_001317185.2 link	c.-1601C>G		5_prime_UTR_variant	Exon 1 of 16		NP_001304114.1
CDH1	NM_001317186.2 link	c.-1805C>G		5_prime_UTR_variant	Exon 1 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDH1	ENST00000261769.10 link	c.15C>G	p.Ser5Arg	missense_variant	Exon 1 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6 link	c.15C>G	p.Ser5Arg	missense_variant	Exon 1 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5 link	n.15C>G		non_coding_transcript_exon_variant	Exon 1 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5 link	n.15C>G		non_coding_transcript_exon_variant	Exon 1 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000772

AC:

AN:

129570

AF XY:

0.0000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000207

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1382430

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

682538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31304

American (AMR)

AF:

0.00

AC:

AN:

35898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25124

East Asian (EAS)

AF:

0.00

AC:

AN:

35744

South Asian (SAS)

AF:

0.00

AC:

AN:

79066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4082

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1079026

Other (OTH)

AF:

0.00

AC:

AN:

57716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Sep 24, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S5R variant (also known as c.15C>G), located in coding exon 1 of the CDH1 gene, results from a C to G substitution at nucleotide position 15. The serine at codon 5 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

T;T;T;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.62

T;T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;.;.;L

PhyloP100

0.93

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.64

N;.;.;.;N

REVEL

Benign

0.14

Sift

Benign

0.35

T;.;.;.;T

Sift4G

Benign

0.40

T;T;T;T;T

Polyphen

0.0

B;.;.;.;.

Vest4

0.27

MutPred

0.44

Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);

MVP

0.78

MPC

0.48

ClinPred

0.094

GERP RS

3.7

PromoterAI

-0.063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.12

gMVP

0.44

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over