10-53961876-C-A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2

The NM_001384140.1(PCDH15):​c.2885G>T​(p.Arg962Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,608,790 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R962C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0030 ( 9 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 1.20
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 was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-53961877-G-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.009616345).
BP6
Variant 10-53961876-C-A is Benign according to our data. Variant chr10-53961876-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46458.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4, Benign=1}. Variant chr10-53961876-C-A is described in Lovd as [Benign]. Variant chr10-53961876-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00304 (462/152180) while in subpopulation AMR AF = 0.00851 (130/15278). AF 95% confidence interval is 0.00732. There are 2 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDH15NM_033056.4 linkc.2885G>T p.Arg962Leu missense_variant Exon 22 of 33 ENST00000320301.11 NP_149045.3 Q96QU1-1
PCDH15NM_001384140.1 linkc.2885G>T p.Arg962Leu missense_variant Exon 22 of 38 ENST00000644397.2 NP_001371069.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCDH15ENST00000320301.11 linkc.2885G>T p.Arg962Leu missense_variant Exon 22 of 33 1 NM_033056.4 ENSP00000322604.6 Q96QU1-1
PCDH15ENST00000644397.2 linkc.2885G>T p.Arg962Leu missense_variant Exon 22 of 38 NM_001384140.1 ENSP00000495195.1 A0A2R8Y6C0

Frequencies

GnomAD3 genomes
AF:
0.00304
AC:
462
AN:
152062
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00109
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00859
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00340
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00354
Gnomad OTH
AF:
0.00335
GnomAD2 exomes
AF:
0.00267
AC:
671
AN:
250940
AF XY:
0.00273
show subpopulations
Gnomad AFR exome
AF:
0.00117
Gnomad AMR exome
AF:
0.00498
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00189
Gnomad NFE exome
AF:
0.00360
Gnomad OTH exome
AF:
0.00475
GnomAD4 exome
AF:
0.00300
AC:
4377
AN:
1456610
Hom.:
9
Cov.:
29
AF XY:
0.00299
AC XY:
2165
AN XY:
724762
show subpopulations
African (AFR)
AF:
0.000840
AC:
28
AN:
33346
American (AMR)
AF:
0.00501
AC:
224
AN:
44688
Ashkenazi Jewish (ASJ)
AF:
0.0000384
AC:
1
AN:
26068
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39494
South Asian (SAS)
AF:
0.0000466
AC:
4
AN:
85830
European-Finnish (FIN)
AF:
0.00193
AC:
103
AN:
53322
Middle Eastern (MID)
AF:
0.00261
AC:
15
AN:
5750
European-Non Finnish (NFE)
AF:
0.00347
AC:
3847
AN:
1107890
Other (OTH)
AF:
0.00257
AC:
155
AN:
60222
Heterozygous variant carriers
0
205
410
615
820
1025
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
140
280
420
560
700
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00304
AC:
462
AN:
152180
Hom.:
2
Cov.:
32
AF XY:
0.00305
AC XY:
227
AN XY:
74404
show subpopulations
African (AFR)
AF:
0.00111
AC:
46
AN:
41530
American (AMR)
AF:
0.00851
AC:
130
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00340
AC:
36
AN:
10588
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.00354
AC:
241
AN:
67996
Other (OTH)
AF:
0.00331
AC:
7
AN:
2114
Heterozygous variant carriers
0
24
48
71
95
119
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00408
Hom.:
3
Bravo
AF:
0.00304
TwinsUK
AF:
0.00431
AC:
16
ALSPAC
AF:
0.00311
AC:
12
ExAC
AF:
0.00208
AC:
253

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:10
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:5
Jan 26, 2017
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 23, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PCDH15: BP4, BS1, BS2 -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Benign:2
-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 11, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Arg962Leu in exon 22 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.3% (35/11558) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45483395). In addition, a different variant at the same position (p.Arg 962His) has also been identified in 0.7% (73/10320) of African chromosomes (ExAC , http://exac.broadinstitute.org; dbSNP rs45483395). The arginine (Arg) at posit ion 962 is not conserved in mammals or evolutionarily distant species and 5 spec ies (Zebra finch, and 4 fish) carry a leucine (Leu) at this position, raising th e possibility that this change may be tolerated. Additional computational predic tion tools suggest that this variant may not impact the protein. -

Usher syndrome type 1F Benign:2
Nov 11, 2019
Natera, Inc.
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 18, 2021
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Usher syndrome type 1 Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

PCDH15-related disorder Benign:1
Jul 02, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.019
T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.59
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.0096
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.58
.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.9
.;.;.;.;.;.;.;N;.;N;N;.;N;.;.;N;N;N;.;N;N
REVEL
Benign
0.13
Sift
Benign
0.16
.;.;.;.;.;.;.;T;.;T;T;.;T;.;.;T;T;T;.;T;T
Sift4G
Benign
0.23
T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0010, 0.013, 0.023, 0.97, 0.10, 0.039
.;.;.;.;.;.;.;.;.;.;B;.;B;.;.;B;D;D;.;B;B
Vest4
0.32
MVP
0.62
MPC
0.032
ClinPred
0.022
T
GERP RS
1.7
Varity_R
0.25
gMVP
0.52
Mutation Taster
=98/2
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs45483395; hg19: chr10-55721636; API