16-68738303-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_Supporting

The NM_004360.5(CDH1):ā€‹c.55T>Gā€‹(p.Ser19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,397,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000036 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: -1.64
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.108899176).
BS2
High AC in GnomAdExome4 at 5 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/exons MANE Protein UniProt
CDH1NM_004360.5 linkc.55T>G p.Ser19Ala missense_variant 2/16 ENST00000261769.10 NP_004351.1 P12830-1A0A0U2ZQU7B3GN61
CDH1NM_001317184.2 linkc.55T>G p.Ser19Ala missense_variant 2/15 NP_001304113.1 P12830-2B3GN61
CDH1NM_001317185.2 linkc.-1561T>G 5_prime_UTR_variant 2/16 NP_001304114.1 P12830B3GN61Q9UII7
CDH1NM_001317186.2 linkc.-1765T>G 5_prime_UTR_variant 2/15 NP_001304115.1 P12830B3GN61

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkc.55T>G p.Ser19Ala missense_variant 2/161 NM_004360.5 ENSP00000261769.4 P12830-1
CDH1ENST00000422392.6 linkc.55T>G p.Ser19Ala missense_variant 2/151 ENSP00000414946.2 P12830-2
CDH1ENST00000566612.5 linkn.55T>G non_coding_transcript_exon_variant 2/151 ENSP00000454782.1 H3BNC6
CDH1ENST00000566510.5 linkn.55T>G non_coding_transcript_exon_variant 2/155 ENSP00000458139.1 H3BVI7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000636
AC:
1
AN:
157190
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
82962
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:
0.0000439
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000358
AC:
5
AN:
1397286
Hom.:
0
Cov.:
30
AF XY:
0.00000290
AC XY:
2
AN XY:
689382
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:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000371
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 23, 2023In 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 406626). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 19 of the CDH1 protein (p.Ser19Ala). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 01, 2018The p.S19A variant (also known as c.55T>G), located in coding exon 2 of the CDH1 gene, results from a T to G substitution at nucleotide position 55. The serine at codon 19 is replaced by alanine, an amino acid with similar 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
0.071
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
0.18
DANN
Benign
0.60
DEOGEN2
Benign
0.33
T;T;T;.;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.041
N
LIST_S2
Benign
0.34
T;T;T;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.11
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;.;.;.;L
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.49
N;.;.;.;N
REVEL
Benign
0.091
Sift
Benign
0.55
T;.;.;.;T
Sift4G
Benign
0.84
T;T;T;T;T
Polyphen
0.0
B;.;.;.;.
Vest4
0.36
MutPred
0.39
Gain of catalytic residue at S19 (P = 0.0067);Gain of catalytic residue at S19 (P = 0.0067);Gain of catalytic residue at S19 (P = 0.0067);Gain of catalytic residue at S19 (P = 0.0067);Gain of catalytic residue at S19 (P = 0.0067);
MVP
0.57
MPC
0.21
ClinPred
0.040
T
GERP RS
-9.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.061
gMVP
0.20

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.

Other links and lift over

dbSNP: rs1042391377; hg19: chr16-68772206; API