rs10740579

Variant summary

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

The NM_001384140.1(PCDH15):​c.706-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,612,902 control chromosomes in the GnomAD database, including 395,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38563 hom., cov: 31)
Exomes 𝑓: 0.69 ( 356958 hom. )

Consequence

PCDH15
NM_001384140.1 splice_region, intron

Scores

2
Splicing: ADA: 0.00002108
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.274
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 (BayesDel_noAF=-0.84).
BP6
Variant 10-54317449-G-A is Benign according to our data. Variant chr10-54317449-G-A is described in ClinVar as [Benign]. Clinvar id is 46511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54317449-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDH15NM_033056.4 linkuse as main transcriptc.706-8C>T splice_region_variant, intron_variant ENST00000320301.11 NP_149045.3 Q96QU1-1
PCDH15NM_001384140.1 linkuse as main transcriptc.706-8C>T splice_region_variant, 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.706-8C>T splice_region_variant, intron_variant 1 NM_033056.4 ENSP00000322604.6 Q96QU1-1
PCDH15ENST00000644397.2 linkuse as main transcriptc.706-8C>T splice_region_variant, intron_variant NM_001384140.1 ENSP00000495195.1 A0A2R8Y6C0

Frequencies

GnomAD3 genomes
AF:
0.705
AC:
107083
AN:
151820
Hom.:
38522
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.748
Gnomad AMI
AF:
0.889
Gnomad AMR
AF:
0.678
Gnomad ASJ
AF:
0.768
Gnomad EAS
AF:
0.221
Gnomad SAS
AF:
0.579
Gnomad FIN
AF:
0.690
Gnomad MID
AF:
0.810
Gnomad NFE
AF:
0.727
Gnomad OTH
AF:
0.728
GnomAD3 exomes
AF:
0.657
AC:
164526
AN:
250538
Hom.:
56660
AF XY:
0.660
AC XY:
89380
AN XY:
135448
show subpopulations
Gnomad AFR exome
AF:
0.749
Gnomad AMR exome
AF:
0.602
Gnomad ASJ exome
AF:
0.751
Gnomad EAS exome
AF:
0.213
Gnomad SAS exome
AF:
0.598
Gnomad FIN exome
AF:
0.700
Gnomad NFE exome
AF:
0.729
Gnomad OTH exome
AF:
0.700
GnomAD4 exome
AF:
0.692
AC:
1011049
AN:
1460964
Hom.:
356958
Cov.:
49
AF XY:
0.691
AC XY:
502447
AN XY:
726804
show subpopulations
Gnomad4 AFR exome
AF:
0.756
Gnomad4 AMR exome
AF:
0.615
Gnomad4 ASJ exome
AF:
0.753
Gnomad4 EAS exome
AF:
0.190
Gnomad4 SAS exome
AF:
0.597
Gnomad4 FIN exome
AF:
0.696
Gnomad4 NFE exome
AF:
0.716
Gnomad4 OTH exome
AF:
0.692
GnomAD4 genome
AF:
0.705
AC:
107184
AN:
151938
Hom.:
38563
Cov.:
31
AF XY:
0.698
AC XY:
51822
AN XY:
74232
show subpopulations
Gnomad4 AFR
AF:
0.748
Gnomad4 AMR
AF:
0.678
Gnomad4 ASJ
AF:
0.768
Gnomad4 EAS
AF:
0.221
Gnomad4 SAS
AF:
0.580
Gnomad4 FIN
AF:
0.690
Gnomad4 NFE
AF:
0.727
Gnomad4 OTH
AF:
0.725
Alfa
AF:
0.729
Hom.:
16936
Bravo
AF:
0.707
Asia WGS
AF:
0.439
AC:
1528
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 17, 2017- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 02, 2012Inferred frequency = 153/302 (LMM data) -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Usher syndrome type 1F Benign:2
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 01, 2021- -
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
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.82
DANN
Benign
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000021
dbscSNV1_RF
Benign
0.0
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: rs10740579; hg19: chr10-56077209; COSMIC: COSV57299868; API