rs142667566

Positions:

• chr10-53822122-CGTT-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.5601_5603del​(p.Thr1869del) variant causes a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T1867T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (175 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (172 hom.)
• Consequence: PCDH15 NM_033056.4 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:2 B:10 O:1
• 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]

ACMG classification

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	UniProt
PCDH15	NM_033056.4	c.5601_5603del	p.Thr1869del	inframe_deletion	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-1895_4368-1893del		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.5601_5603del	p.Thr1869del	inframe_deletion	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-1895_4368-1893del		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3918 AN: 151976 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0221

GnomAD3 exomes AF: 0.00720 AC: 1811 AN: 251400 Hom.: 72 AF XY: 0.00521 AC XY: 708 AN XY: 135866

Gnomad AFR exome AF: 0.0879

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000915

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00334 AC: 4877 AN: 1461800 Hom.: 172 AF XY: 0.00293 AC XY: 2134 AN XY: 727184

Gnomad4 AFR exome AF: 0.0913

Gnomad4 AMR exome AF: 0.00664

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.000774

Gnomad4 OTH exome AF: 0.00773

GnomAD4 genome AF: 0.0259 AC: 3945 AN: 152094 Hom.: 175 Cov.: 32 AF XY: 0.0257 AC XY: 1909 AN XY: 74376

Gnomad4 AFR AF: 0.0869

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0138 Hom.: 15

Bravo AF: 0.0301

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2 Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	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	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	Invitae	Feb 01, 2024	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

Usher syndrome type 1F Pathogenic:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 13, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -

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

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs113363047; hg19: chr10-55581882;