chr10-53822423-GGAGGAGCAA-G

Variant names:

• chr10-53822423-GGAGGAGCAA-G
• rs557936064
• NM_033056.4:c.5294_5302delTTGCTCCTC

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_033056.4(PCDH15):​c.5294_5302delTTGCTCCTC​(p.Leu1765_Pro1767del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,585,476 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: PCDH15 NM_033056.4 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.97
• Publications: 2 publications found

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]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_033056.4
• BP6: Variant 10-53822423-GGAGGAGCAA-G is Benign according to our data. Variant chr10-53822423-GGAGGAGCAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.5294_5302delTTGCTCCTC	p.Leu1765_Pro1767del	disruptive_inframe_deletion	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2202_4368-2194delTTGCTCCTC		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.5315_5323delTTGCTCCTC	p.Leu1772_Pro1774del	disruptive_inframe_deletion	Exon 35 of 35	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.5294_5302delTTGCTCCTC	p.Leu1765_Pro1767del	disruptive_inframe_deletion	Exon 33 of 33	ENSP00000322604.6
	PCDH15	ENST00000463095.2	TSL:1	n.2313_2321delTTGCTCCTC		non_coding_transcript_exon	Exon 10 of 10
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2202_4368-2194delTTGCTCCTC		intron	N/A	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 151416 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000562

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.000855

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00129 AC: 261 AN: 202002 AF XY: 0.00125

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.00202 AC: 2901 AN: 1433942 Hom.: 2 AF XY: 0.00194 AC XY: 1378 AN XY: 711240

African (AFR) AF: 0.000312 AC: 10 AN: 32008

American (AMR) AF: 0.000983 AC: 40 AN: 40672

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 4 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 37386

South Asian (SAS) AF: 0.0000479 AC: 4 AN: 83516

European-Finnish (FIN) AF: 0.00209 AC: 108 AN: 51566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00239 AC: 2626 AN: 1097944

Other (OTH) AF: 0.00183 AC: 109 AN: 59416

GnomAD4 genome AF: 0.00125 AC: 190 AN: 151534 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 85 AN XY: 74080

African (AFR) AF: 0.000560 AC: 23 AN: 41078

American (AMR) AF: 0.000854 AC: 13 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 67916

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 17, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25307757)

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCDH15: BP3

Jan 09, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Apr 03, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Leu1765_Pro1767del in exon 33 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.4% (96/24474) of Europ ean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org).

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Benign:1

May 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCDH15-related disorder Benign:1

Jan 08, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This 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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=168/32	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs557936064; hg19: chr10-55582183;