rs1060501223

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting

The NM_004360.5(CDH1):c.145G>A(p.Gly49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000839 in 1,550,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.21

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

BS2

High AC in GnomAdExome4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5 link	c.145G>A	p.Gly49Ser	missense_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 link	c.145G>A	p.Gly49Ser	missense_variant	Exon 2 of 15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 link	c.-1471G>A		5_prime_UTR_variant	Exon 2 of 16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 link	c.-1675G>A		5_prime_UTR_variant	Exon 2 of 15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH1	ENST00000261769.10 link	c.145G>A	p.Gly49Ser	missense_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6 link	c.145G>A	p.Gly49Ser	missense_variant	Exon 2 of 15	1		ENSP00000414946.2	P12830-2
CDH1	ENST00000566612.5 link	n.145G>A		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1	H3BNC6
CDH1	ENST00000566510.5 link	n.145G>A		non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000458139.1	H3BVI7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000194

AC:

AN:

154386

Hom.:

AF XY:

0.0000245

AC XY:

AN XY:

81720

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 SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000787

AC:

AN:

1397706

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

689268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:1

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 49 of the CDH1 protein (p.Gly49Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 406627). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Apr 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G49S variant (also known as c.145G>A), located in coding exon 2 of the CDH1 gene, results from a G to A substitution at nucleotide position 145. The glycine at codon 49 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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

0.27

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;T;T;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.077

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.85

T;T;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.5

M;.;.;.;M

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.3

N;.;.;.;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.024

D;.;.;.;D

Sift4G

Uncertain

0.045

D;D;D;D;D

Polyphen

0.93

P;.;.;.;.

Vest4

0.71

MutPred

0.85

Gain of phosphorylation at G49 (P = 0.0422);Gain of phosphorylation at G49 (P = 0.0422);Gain of phosphorylation at G49 (P = 0.0422);Gain of phosphorylation at G49 (P = 0.0422);Gain of phosphorylation at G49 (P = 0.0422);

MVP

0.83

MPC

0.52

ClinPred

0.84

GERP RS

2.8

Varity_R

0.20

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over