10-53866870-GAA-GAAA

Variant names:

• chr10-53866870-G-GA
• rs5785023
• NM_033056.4:c.3502-14dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.3502-14dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,477,920 control chromosomes in the GnomAD database, including 32,181 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6332 hom., cov: 22)
  • Exomes 𝑓: 0.18 (25849 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.936
• 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 -16 ACMG points.

• BP6: Variant 10-53866870-G-GA is Benign according to our data. Variant chr10-53866870-G-GA is described in ClinVar as Benign. ClinVar VariationId is 46468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.3502-14dupT		intron_variant	Intron 26 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.3502-14dupT		intron_variant	Intron 26 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3502-14_3502-13insT		intron_variant	Intron 26 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.3502-14_3502-13insT		intron_variant	Intron 26 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 38704 AN: 149830 Hom.: 6331 Cov.: 22

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.241

GnomAD2 exomes AF: 0.262 AC: 60911 AN: 232130 AF XY: 0.254

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.184 AC: 244905 AN: 1327986 Hom.: 25849 Cov.: 23 AF XY: 0.188 AC XY: 125428 AN XY: 667038

African (AFR) AF: 0.335 AC: 9842 AN: 29358

American (AMR) AF: 0.358 AC: 15052 AN: 42030

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3591 AN: 24902

East Asian (EAS) AF: 0.736 AC: 25210 AN: 34272

South Asian (SAS) AF: 0.317 AC: 25748 AN: 81180

European-Finnish (FIN) AF: 0.194 AC: 10126 AN: 52224

Middle Eastern (MID) AF: 0.154 AC: 837 AN: 5426

European-Non Finnish (NFE) AF: 0.143 AC: 143196 AN: 1003222

Other (OTH) AF: 0.204 AC: 11303 AN: 55372

GnomAD4 genome AF: 0.258 AC: 38743 AN: 149934 Hom.: 6332 Cov.: 22 AF XY: 0.267 AC XY: 19476 AN XY: 73050

African (AFR) AF: 0.359 AC: 14713 AN: 40952

American (AMR) AF: 0.292 AC: 4397 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 557 AN: 3448

East Asian (EAS) AF: 0.756 AC: 3849 AN: 5088

South Asian (SAS) AF: 0.352 AC: 1674 AN: 4752

European-Finnish (FIN) AF: 0.206 AC: 2064 AN: 10008

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10724 AN: 67346

Other (OTH) AF: 0.244 AC: 507 AN: 2076

Alfa AF: 0.116 Hom.: 212

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Oct 29, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 29, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3502-14dupT variant is classified as benign because it has been identified in 26.4% of total chromosomes, including 9873 homozygotes, by gnomAD (http://gn omad-beta.broadinstitute.org/) -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PCDH15 c.3502-14dupT variant involves the duplication of an intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 29147/114904 control chromosomes (3844 homozygotes) at a frequency of 0.2536639, which is approximately 80 times the estimated maximal expected allele frequency of a pathogenic PCDH15 variant (0.0031623), strong evidence that this variant is a benign polymorphism. In addition, one clinical diagnostic laboratory/reputable database has classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Autosomal recessive nonsyndromic hearing loss 23 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5785023; hg19: chr10-55626630;