chr10-53822000-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033056.4(PCDH15):​c.5726G>A​(p.Arg1909His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.99
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11380139).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDH15NM_033056.4 linkc.5726G>A p.Arg1909His missense_variant Exon 33 of 33 ENST00000320301.11 NP_149045.3 Q96QU1-1
PCDH15NM_001384140.1 linkc.4368-1770G>A intron_variant Intron 32 of 37 ENST00000644397.2 NP_001371069.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCDH15ENST00000320301.11 linkc.5726G>A p.Arg1909His missense_variant Exon 33 of 33 1 NM_033056.4 ENSP00000322604.6 Q96QU1-1
PCDH15ENST00000644397.2 linkc.4368-1770G>A intron_variant Intron 32 of 37 NM_001384140.1 ENSP00000495195.1 A0A2R8Y6C0

Frequencies

GnomAD3 genomes
AF:
0.0000921
AC:
14
AN:
152044
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.000478
GnomAD3 exomes
AF:
0.000127
AC:
32
AN:
251298
Hom.:
0
AF XY:
0.0000884
AC XY:
12
AN XY:
135812
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000550
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:
0.0000880
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000133
AC:
194
AN:
1461676
Hom.:
0
Cov.:
32
AF XY:
0.000120
AC XY:
87
AN XY:
727148
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000626
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:
0.000127
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.0000921
AC:
14
AN:
152044
Hom.:
0
Cov.:
32
AF XY:
0.0000943
AC XY:
7
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.000197
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:
0.000478
Alfa
AF:
0.000189
Hom.:
0
Bravo
AF:
0.000215
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Usher syndrome type 1F Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Feb 03, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylJan 08, 2018- -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 24, 2025Reported in published literature (as R1889H using alternate nomenclature) as a single heterozygous variant in a patient with retinitis pigmentosa who had a different suggested genetic etiology for the phenotype (PMID: 25692139); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25692139) -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2025- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 14, 2016Variant classified as Uncertain Significance - Favor Benign. The p.Arg1909His va riant in PCDH15 has been identified by our laboratory in one individual with hea ring loss who did not have a second PCDH15 variant. This variant has also been i dentified in 14/121438 chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs145851144). Computational prediction tools and conservation analyses suggest that the p.Arg1909His variant may not impact the protein, though this information is not predictive enough to rule out pathog enicity. In summary, while the clinical significance of the p.Arg1909His variant is uncertain, these data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
14
DANN
Benign
0.87
DEOGEN2
Benign
0.0032
.;T;.;.;.;.;.;.;T
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.54
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.83
T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.11
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
.;.;.;.;.;.;.;.;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.10
N;.;.;N;N;N;.;N;N
REVEL
Benign
0.082
Sift
Benign
0.097
T;.;.;T;T;T;.;T;T
Sift4G
Uncertain
0.015
D;D;D;D;D;D;D;D;D
Polyphen
0.89
P;.;.;P;P;P;.;P;P
Vest4
0.16
MVP
0.67
MPC
0.031
ClinPred
0.046
T
GERP RS
2.4
Varity_R
0.021
gMVP
0.24

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: rs145851144; hg19: chr10-55581760; COSMIC: COSV100224390; COSMIC: COSV100224390; API