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GeneBe

rs61731389

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033056.4(PCDH15):c.1910A>G(p.Asn637Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0271 in 1,612,316 control chromosomes in the GnomAD database, including 791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 86 hom., cov: 32)
Exomes 𝑓: 0.027 ( 705 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

7
8

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.18
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009124845).
BP6
Variant 10-54132882-T-C is Benign according to our data. Variant chr10-54132882-T-C is described in ClinVar as [Benign]. Clinvar id is 46448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54132882-T-C is described in Lovd as [Benign].
BA1
GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCDH15NM_033056.4 linkuse as main transcriptc.1910A>G p.Asn637Ser missense_variant 15/33 ENST00000320301.11
PCDH15NM_001384140.1 linkuse as main transcriptc.1910A>G p.Asn637Ser missense_variant 15/38 ENST00000644397.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCDH15ENST00000320301.11 linkuse as main transcriptc.1910A>G p.Asn637Ser missense_variant 15/331 NM_033056.4 Q96QU1-1
PCDH15ENST00000644397.2 linkuse as main transcriptc.1910A>G p.Asn637Ser missense_variant 15/38 NM_001384140.1

Frequencies

GnomAD3 genomes
AF:
0.0295
AC:
4487
AN:
151962
Hom.:
86
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0356
Gnomad AMI
AF:
0.00548
Gnomad AMR
AF:
0.0279
Gnomad ASJ
AF:
0.0326
Gnomad EAS
AF:
0.00155
Gnomad SAS
AF:
0.0487
Gnomad FIN
AF:
0.0270
Gnomad MID
AF:
0.0854
Gnomad NFE
AF:
0.0270
Gnomad OTH
AF:
0.0397
GnomAD3 exomes
AF:
0.0275
AC:
6832
AN:
248534
Hom.:
131
AF XY:
0.0290
AC XY:
3899
AN XY:
134282
show subpopulations
Gnomad AFR exome
AF:
0.0370
Gnomad AMR exome
AF:
0.0174
Gnomad ASJ exome
AF:
0.0332
Gnomad EAS exome
AF:
0.00205
Gnomad SAS exome
AF:
0.0485
Gnomad FIN exome
AF:
0.0238
Gnomad NFE exome
AF:
0.0274
Gnomad OTH exome
AF:
0.0344
GnomAD4 exome
AF:
0.0269
AC:
39249
AN:
1460236
Hom.:
705
Cov.:
34
AF XY:
0.0277
AC XY:
20129
AN XY:
726292
show subpopulations
Gnomad4 AFR exome
AF:
0.0367
Gnomad4 AMR exome
AF:
0.0179
Gnomad4 ASJ exome
AF:
0.0347
Gnomad4 EAS exome
AF:
0.00104
Gnomad4 SAS exome
AF:
0.0496
Gnomad4 FIN exome
AF:
0.0238
Gnomad4 NFE exome
AF:
0.0256
Gnomad4 OTH exome
AF:
0.0305
GnomAD4 genome
AF:
0.0295
AC:
4491
AN:
152080
Hom.:
86
Cov.:
32
AF XY:
0.0303
AC XY:
2256
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0356
Gnomad4 AMR
AF:
0.0279
Gnomad4 ASJ
AF:
0.0326
Gnomad4 EAS
AF:
0.00155
Gnomad4 SAS
AF:
0.0489
Gnomad4 FIN
AF:
0.0270
Gnomad4 NFE
AF:
0.0270
Gnomad4 OTH
AF:
0.0393
Alfa
AF:
0.0287
Hom.:
125
Bravo
AF:
0.0291
TwinsUK
AF:
0.0216
AC:
80
ALSPAC
AF:
0.0228
AC:
88
ESP6500AA
AF:
0.0365
AC:
161
ESP6500EA
AF:
0.0281
AC:
242
ExAC
AF:
0.0280
AC:
3396
Asia WGS
AF:
0.0220
AC:
77
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 18, 2014This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 23, 2009- -
Usher syndrome type 1F Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 01, 2021- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Jan 10, 2020- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMar 21, 2019- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Autosomal recessive nonsyndromic hearing loss 23 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Usher syndrome type 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.55
T
BayesDel_noAF
Benign
-0.53
Cadd
Benign
22
Dann
Uncertain
1.0
DEOGEN2
Benign
0.018
T;.;.;.;.;T;T;.;T;T;.;.;T;.;T;.;.;.;.;T;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN
Benign
0.0091
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.58
T
REVEL
Benign
0.17
Sift4G
Uncertain
0.028
D;.;D;D;D;D;T;T;T;D;D;T;D;D;D;D;D;D;D;D;D
Polyphen
0.95, 0.94, 0.97, 1.0, 0.74, 0.86
.;.;.;.;.;.;.;.;.;.;.;P;.;P;.;D;D;D;.;P;P
Vest4
0.69
MPC
0.070
ClinPred
0.089
T
GERP RS
3.2
Varity_R
0.15
gMVP
0.31

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: rs61731389; hg19: chr10-55892642; COSMIC: COSV57343468; API