chr16-89179500-G-T
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_004933.3(CDH15):c.127G>T(p.Val43Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,613,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V43M) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
CDH15
NM_004933.3 missense
NM_004933.3 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 4.60
Genes affected
CDH15 (HGNC:1754): (cadherin 15) This gene is a member of the cadherin superfamily of genes, encoding calcium-dependent intercellular adhesion glycoproteins. Cadherins consist of an extracellular domain containing 5 cadherin domains, a transmembrane region, and a conserved cytoplasmic domain. Transcripts from this particular cadherin are expressed in myoblasts and upregulated in myotubule-forming cells. The protein is thought to be essential for the control of morphogenetic processes, specifically myogenesis, and may provide a trigger for terminal muscle cell differentiation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAd4 at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH15 | NM_004933.3 | c.127G>T | p.Val43Leu | missense_variant | 2/14 | ENST00000289746.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH15 | ENST00000289746.3 | c.127G>T | p.Val43Leu | missense_variant | 2/14 | 1 | NM_004933.3 | P1 | |
CDH15 | ENST00000521087.5 | n.192G>T | non_coding_transcript_exon_variant | 2/3 | 5 | ||||
CDH15 | ENST00000524089.1 | n.192G>T | non_coding_transcript_exon_variant | 2/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152232Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000480 AC: 12AN: 250062Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135336
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GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461002Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34AN XY: 726818
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GnomAD4 genome AF: 0.0000788 AC: 12AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74378
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2023 | The c.127G>T (p.V43L) alteration is located in exon 2 (coding exon 2) of the CDH15 gene. This alteration results from a G to T substitution at nucleotide position 127, causing the valine (V) at amino acid position 43 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of sheet (P = 0.0166);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at