chr16-68737459-T-A
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_004360.5(CDH1):c.44T>A(p.Leu15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,536,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
Publications
- blepharocheilodontic syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
- CDH1-related diffuse gastric and lobular breast cancer syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- hereditary diffuse gastric adenocarcinomaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
- cleft soft palateInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- orofacial cleft 3Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- blepharocheilodontic syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.44T>A | p.Leu15Gln | missense_variant | Exon 1 of 16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.44T>A | p.Leu15Gln | missense_variant | Exon 1 of 15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.-1572T>A | 5_prime_UTR_variant | Exon 1 of 16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1776T>A | 5_prime_UTR_variant | Exon 1 of 15 | NP_001304115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.44T>A | p.Leu15Gln | missense_variant | Exon 1 of 16 | 1 | NM_004360.5 | ENSP00000261769.4 | ||
CDH1 | ENST00000422392.6 | c.44T>A | p.Leu15Gln | missense_variant | Exon 1 of 15 | 1 | ENSP00000414946.2 | |||
CDH1 | ENST00000566612.5 | n.44T>A | non_coding_transcript_exon_variant | Exon 1 of 15 | 1 | ENSP00000454782.1 | ||||
CDH1 | ENST00000566510.5 | n.44T>A | non_coding_transcript_exon_variant | Exon 1 of 15 | 5 | ENSP00000458139.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00 AC: 0AN: 131304 AF XY: 0.00
GnomAD4 exome AF: 0.00000217 AC: 3AN: 1384678Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1AN XY: 683942 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The p.L15Q variant (also known as c.44T>A), located in coding exon 1 of the CDH1 gene, results from a T to A substitution at nucleotide position 44. The leucine at codon 15 is replaced by glutamine, an amino acid with dissimilar properties. This amino acid position is highly 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. -
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Hereditary diffuse gastric adenocarcinoma Uncertain:1
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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 576714). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 15 of the CDH1 protein (p.Leu15Gln). -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at