chr16-89179533-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004933.3(CDH15):​c.160G>A​(p.Val54Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,610,922 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V54L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00035 ( 5 hom. )

Consequence

CDH15
NM_004933.3 missense

Scores

8
11

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.06
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010460734).
BP6
Variant 16-89179533-G-A is Benign according to our data. Variant chr16-89179533-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 739776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDH15NM_004933.3 linkuse as main transcriptc.160G>A p.Val54Ile missense_variant 2/14 ENST00000289746.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH15ENST00000289746.3 linkuse as main transcriptc.160G>A p.Val54Ile missense_variant 2/141 NM_004933.3 P1
CDH15ENST00000521087.5 linkuse as main transcriptn.225G>A non_coding_transcript_exon_variant 2/35
CDH15ENST00000524089.1 linkuse as main transcriptn.225G>A non_coding_transcript_exon_variant 2/52

Frequencies

GnomAD3 genomes
AF:
0.000677
AC:
103
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00159
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00704
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000696
AC:
173
AN:
248442
Hom.:
4
AF XY:
0.000893
AC XY:
120
AN XY:
134424
show subpopulations
Gnomad AFR exome
AF:
0.00130
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00456
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000894
Gnomad OTH exome
AF:
0.000331
GnomAD4 exome
AF:
0.000352
AC:
513
AN:
1458606
Hom.:
5
Cov.:
32
AF XY:
0.000474
AC XY:
344
AN XY:
725368
show subpopulations
Gnomad4 AFR exome
AF:
0.00138
Gnomad4 AMR exome
AF:
0.000135
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00431
Gnomad4 FIN exome
AF:
0.0000190
Gnomad4 NFE exome
AF:
0.0000486
Gnomad4 OTH exome
AF:
0.000548
GnomAD4 genome
AF:
0.000676
AC:
103
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.000846
AC XY:
63
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00159
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00705
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000137
Hom.:
0
Bravo
AF:
0.000518
ESP6500AA
AF:
0.00159
AC:
7
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000923
AC:
112
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2019- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024CDH15: BS2 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.064
T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.30
T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.010
T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.71
N
REVEL
Benign
0.20
Sift
Uncertain
0.013
D
Sift4G
Uncertain
0.019
D
Polyphen
1.0
D
Vest4
0.14
MVP
0.73
MPC
0.20
ClinPred
0.039
T
GERP RS
4.5
Varity_R
0.14
gMVP
0.39

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: rs138572161; hg19: chr16-89245941; COSMIC: COSV57027707; API