rs113363047
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBA1
The NM_033056.4(PCDH15):c.5601_5603delAAC(p.Thr1868del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,613,894 control chromosomes in the GnomAD database, including 347 homozygotes. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.026 ( 175 hom., cov: 32)
Exomes 𝑓: 0.0033 ( 172 hom. )
Consequence
PCDH15
NM_033056.4 disruptive_inframe_deletion
NM_033056.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.86
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 -15 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_033056.4. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant 10-53822122-CGTT-C is Benign according to our data. Variant chr10-53822122-CGTT-C is described in ClinVar as [Benign]. Clinvar id is 46505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53822122-CGTT-C is described in Lovd as [Likely_benign]. Variant chr10-53822122-CGTT-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.5601_5603delAAC | p.Thr1868del | disruptive_inframe_deletion | 33/33 | ENST00000320301.11 | NP_149045.3 | |
PCDH15 | NM_001384140.1 | c.4368-1895_4368-1893delAAC | intron_variant | ENST00000644397.2 | NP_001371069.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.5601_5603delAAC | p.Thr1868del | disruptive_inframe_deletion | 33/33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.4368-1895_4368-1893delAAC | intron_variant | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes AF: 0.0258 AC: 3918AN: 151976Hom.: 170 Cov.: 32
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GnomAD3 exomes AF: 0.00720 AC: 1811AN: 251400Hom.: 72 AF XY: 0.00521 AC XY: 708AN XY: 135866
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GnomAD4 exome AF: 0.00334 AC: 4877AN: 1461800Hom.: 172 AF XY: 0.00293 AC XY: 2134AN XY: 727184
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GnomAD4 genome AF: 0.0259 AC: 3945AN: 152094Hom.: 175 Cov.: 32 AF XY: 0.0257 AC XY: 1909AN XY: 74376
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ClinVar
Significance: Benign
Submissions summary: Pathogenic:2Benign:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 17, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 18, 2021 | Variant summary: PCDH15 c.5601_5603delAAC (p.Thr1869del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0072 in 251400 control chromosomes, predominantly at a frequency of 0.088 within the African or African-American subpopulation in the gnomAD database, including 72 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although cited in the literature, to our knowledge, no occurrence of c.5601_5603delAAC in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 17, 2011 | Thr1869del in exon 33 of PCDH15: This variant has been reported in 4 individuals with Usher syndrome and one individual with hearing loss, and was absent in 100 control chromosomes (Ouyang 2005, Zheng 2005, Bonnet 2011). However, three of t he Usher syndrome probands did not have a second PCDH15 variant identified, incl uding two probands who had pathogenic variants in another gene. The fourth Usher syndrome proband carried the variant in the compound heterozygous state with an other PCDH15 variant which we feel does not have evidence for pathogenicity. The proband with hearing loss carried this variant in the homozygous state; this is inconsistent with the phenotype expected of two pathogenic PCDH15 variants. Thi s variant has also been identified by our laboratory in two probands, both of wh om carry pathogenic or likely pathogenic variants in other genes. Furthermore, G ET-Evidence database (http://evidence.personalgenomes.org) reports this variant at a frequency of 6% (8/128 chromosomes). In summary, based upon the observation s to date, we feel this variant is likely benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2016 | This 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. - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 06, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 24, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 12, 2018 | - - |
Usher syndrome type 1F Pathogenic:1Benign:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2005 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 13, 2020 | - - |
USHER SYNDROME, TYPE ID/F, DIGENIC Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2005 | - - |
Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 04, 2022 | - - |
Usher syndrome type 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at