chr16-89179500-G-T

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

Scores

1
5
13

Clinical Significance

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

Conservation

PhyloP100: 4.60
Variant links:
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]

Genome browser will be placed here

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
CDH15NM_004933.3 linkuse as main transcriptc.127G>T p.Val43Leu missense_variant 2/14 ENST00000289746.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH15ENST00000289746.3 linkuse as main transcriptc.127G>T p.Val43Leu missense_variant 2/141 NM_004933.3 P1
CDH15ENST00000521087.5 linkuse as main transcriptn.192G>T non_coding_transcript_exon_variant 2/35
CDH15ENST00000524089.1 linkuse as main transcriptn.192G>T non_coding_transcript_exon_variant 2/52

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000480
AC:
12
AN:
250062
Hom.:
0
AF XY:
0.0000665
AC XY:
9
AN XY:
135336
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000107
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461002
Hom.:
0
Cov.:
32
AF XY:
0.0000468
AC XY:
34
AN XY:
726818
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000486
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000941
AC XY:
7
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000457
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

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 submitterclinical testingAmbry GeneticsFeb 27, 2023The 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.096
T
Eigen
Benign
0.039
Eigen_PC
Benign
0.016
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.65
T
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.59
D
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.23
Sift
Benign
0.17
T
Sift4G
Benign
0.11
T
Polyphen
0.92
P
Vest4
0.51
MutPred
0.40
Gain of sheet (P = 0.0166);
MVP
0.55
MPC
0.12
ClinPred
0.54
D
GERP RS
4.6
Varity_R
0.088
gMVP
0.65

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: rs138610425; hg19: chr16-89245908; API