chr16-89179418-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004933.3(CDH15):ā€‹c.45C>Gā€‹(p.Ser15Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

CDH15
NM_004933.3 missense, splice_region

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0780
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.33842835).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDH15NM_004933.3 linkuse as main transcriptc.45C>G p.Ser15Arg missense_variant, splice_region_variant 2/14 ENST00000289746.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH15ENST00000289746.3 linkuse as main transcriptc.45C>G p.Ser15Arg missense_variant, splice_region_variant 2/141 NM_004933.3 P1
CDH15ENST00000521087.5 linkuse as main transcriptn.110C>G splice_region_variant, non_coding_transcript_exon_variant 2/35
CDH15ENST00000524089.1 linkuse as main transcriptn.110C>G splice_region_variant, non_coding_transcript_exon_variant 2/52

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152234
Hom.:
0
Cov.:
33
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249738
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135252
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:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461260
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
726918
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152234
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74374
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000225
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 30, 2022The c.45C>G (p.S15R) alteration is located in exon 2 (coding exon 2) of the CDH15 gene. This alteration results from a C to G substitution at nucleotide position 45, causing the serine (S) at amino acid position 15 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Benign
-0.098
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
8.9
DANN
Benign
0.94
DEOGEN2
Benign
0.078
T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.48
T
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.34
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.50
N
REVEL
Benign
0.17
Sift
Benign
0.20
T
Sift4G
Benign
0.28
T
Polyphen
0.15
B
Vest4
0.59
MutPred
0.63
Gain of sheet (P = 1e-04);
MVP
0.74
MPC
0.033
ClinPred
0.056
T
GERP RS
1.9
Varity_R
0.064
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs775705281; hg19: chr16-89245826; API