rs191736346

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033056.4(PCDH15):​c.5603C>T​(p.Thr1868Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000698 in 1,597,172 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00038 ( 2 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

3
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 2.86
Variant links:
Genes affected
PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0042761564).
BP6
Variant 10-53822123-G-A is Benign according to our data. Variant chr10-53822123-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46506.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}. Variant chr10-53822123-G-A is described in Lovd as [Benign]. Variant chr10-53822123-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00386 (559/144692) while in subpopulation AFR AF= 0.015 (519/34708). AF 95% confidence interval is 0.0139. There are 3 homozygotes in gnomad4. There are 257 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDH15NM_033056.4 linkuse as main transcriptc.5603C>T p.Thr1868Met missense_variant 33/33 ENST00000320301.11 NP_149045.3
PCDH15NM_001384140.1 linkuse as main transcriptc.4368-1893C>T intron_variant ENST00000644397.2 NP_001371069.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCDH15ENST00000320301.11 linkuse as main transcriptc.5603C>T p.Thr1868Met missense_variant 33/331 NM_033056.4 ENSP00000322604 Q96QU1-1
PCDH15ENST00000644397.2 linkuse as main transcriptc.4368-1893C>T intron_variant NM_001384140.1 ENSP00000495195

Frequencies

GnomAD3 genomes
AF:
0.00386
AC:
558
AN:
144618
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0150
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00189
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:
0.000103
Gnomad OTH
AF:
0.00250
GnomAD3 exomes
AF:
0.000978
AC:
246
AN:
251408
Hom.:
3
AF XY:
0.000670
AC XY:
91
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.0121
Gnomad AMR exome
AF:
0.000896
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.000978
GnomAD4 exome
AF:
0.000383
AC:
556
AN:
1452480
Hom.:
2
Cov.:
32
AF XY:
0.000321
AC XY:
232
AN XY:
723090
show subpopulations
Gnomad4 AFR exome
AF:
0.0134
Gnomad4 AMR exome
AF:
0.00122
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000378
Gnomad4 SAS exome
AF:
0.0000929
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000522
Gnomad4 OTH exome
AF:
0.000790
GnomAD4 genome
AF:
0.00386
AC:
559
AN:
144692
Hom.:
3
Cov.:
32
AF XY:
0.00363
AC XY:
257
AN XY:
70794
show subpopulations
Gnomad4 AFR
AF:
0.0150
Gnomad4 AMR
AF:
0.00189
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00247
Alfa
AF:
0.000426
Hom.:
2
Bravo
AF:
0.00413
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.00128
AC:
153
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 13, 2017Thr1868Met in exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 1.5% (132/8652) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191736346). -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 09, 2015- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 14, 2018- -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 15, 2019This variant is associated with the following publications: (PMID: 26969326) -
Usher syndrome type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.012
.;T;.;.;.;.;.;.;T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.83
T;T;T;T;T;T;T;T;T
MetaRNN
Benign
0.0043
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.5
.;.;.;.;.;.;.;.;L
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.040
N;.;.;N;N;N;.;N;N
REVEL
Benign
0.12
Sift
Uncertain
0.0040
D;.;.;D;D;D;.;D;D
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D;D;D
Polyphen
0.88
P;.;.;P;P;P;.;P;P
Vest4
0.12
MVP
0.74
MPC
0.028
ClinPred
0.017
T
GERP RS
2.7
Varity_R
0.037
gMVP
0.22

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: rs191736346; hg19: chr10-55581883; COSMIC: COSV57288412; COSMIC: COSV57288412; API