rs1554820012

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP6_Very_Strong

The ENST00000320301.11(PCDH15):​c.5280_5342del​(p.Ala1761_Pro1781del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,572,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (β˜…β˜…). Synonymous variant affecting the same amino acid position (i.e. P1760P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

PCDH15
ENST00000320301.11 inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.97
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 Likely_benign. Variant got -6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 10-53822383-GGGAGGAGGACAAAAAAGAGAAAAAGGAGAAATGTCAGGAGGAGGAGCAAGAGGAGCAGGAGCA-G is Benign according to our data. Variant chr10-53822383-GGGAGGAGGACAAAAAAGAGAAAAAGGAGAAATGTCAGGAGGAGGAGCAAGAGGAGCAGGAGCA-G is described in ClinVar as [Likely_benign]. Clinvar id is 179750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDH15NM_033056.4 linkuse as main transcriptc.5280_5342del p.Ala1761_Pro1781del inframe_deletion 33/33 ENST00000320301.11 NP_149045.3
PCDH15NM_001384140.1 linkuse as main transcriptc.4368-2216_4368-2154del 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.5280_5342del p.Ala1761_Pro1781del inframe_deletion 33/331 NM_033056.4 ENSP00000322604 Q96QU1-1
PCDH15ENST00000644397.2 linkuse as main transcriptc.4368-2216_4368-2154del intron_variant NM_001384140.1 ENSP00000495195

Frequencies

GnomAD3 genomes
AF:
0.00121
AC:
183
AN:
151128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00439
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000663
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:
0.0000295
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000319
AC:
58
AN:
182056
Hom.:
0
AF XY:
0.000225
AC XY:
22
AN XY:
97826
show subpopulations
Gnomad AFR exome
AF:
0.00520
Gnomad AMR exome
AF:
0.0000371
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000992
AC:
141
AN:
1421496
Hom.:
0
AF XY:
0.0000895
AC XY:
63
AN XY:
703916
show subpopulations
Gnomad4 AFR exome
AF:
0.00371
Gnomad4 AMR exome
AF:
0.000184
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:
0.00000275
Gnomad4 OTH exome
AF:
0.000170
GnomAD4 genome
AF:
0.00121
AC:
183
AN:
151246
Hom.:
0
Cov.:
32
AF XY:
0.00104
AC XY:
77
AN XY:
73868
show subpopulations
Gnomad4 AFR
AF:
0.00437
Gnomad4 AMR
AF:
0.0000662
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000295
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000334
Hom.:
0

ClinVar

Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 27, 2022See Variant Classification Assertion Criteria. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 28, 2014Ala1761_Pro1781del in exon 33 of PCDH15: This variant is not expected to have cl inical significance because it has been identified in 0.8% (66/8214) of European American chromosomes and in 0.9% (39/4326) of African American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). In addit ion, the exon 33 region of PCDH15 is not conserved across species. -
PCDH15-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 19, 2023This 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). -
Usher syndrome type 1F Benign:1
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Feb 22, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs1554820012; hg19: chr10-55582143; API