rs10825269

Variant names:

• chr10-54195850-C-T
• rs10825269
• NM_033056.4:c.1138G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.1138G>A​(p.Gly380Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,612,490 control chromosomes in the GnomAD database, including 22,139 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G380G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (5424 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16715 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 2.78
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051817894).
• BP6: Variant 10-54195850-C-T is Benign according to our data. Variant chr10-54195850-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1138G>A	p.Gly380Ser	missense_variant	Exon 11 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1138G>A	p.Gly380Ser	missense_variant	Exon 11 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1138G>A	p.Gly380Ser	missense_variant	Exon 11 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1138G>A	p.Gly380Ser	missense_variant	Exon 11 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33582 AN: 151810 Hom.: 5410 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0907

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.162 AC: 40803 AN: 251322 AF XY: 0.156

Gnomad AFR exome AF: 0.459

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.0950

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.138 AC: 202015 AN: 1460562 Hom.: 16715 Cov.: 32 AF XY: 0.138 AC XY: 99944 AN XY: 726670

African (AFR) AF: 0.470 AC: 15704 AN: 33414

American (AMR) AF: 0.210 AC: 9375 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 3082 AN: 26120

East Asian (EAS) AF: 0.0668 AC: 2652 AN: 39672

South Asian (SAS) AF: 0.179 AC: 15459 AN: 86226

European-Finnish (FIN) AF: 0.113 AC: 6013 AN: 53412

Middle Eastern (MID) AF: 0.170 AC: 978 AN: 5756

European-Non Finnish (NFE) AF: 0.126 AC: 139500 AN: 1110914

Other (OTH) AF: 0.153 AC: 9252 AN: 60328

GnomAD4 genome AF: 0.221 AC: 33633 AN: 151928 Hom.: 5424 Cov.: 32 AF XY: 0.218 AC XY: 16176 AN XY: 74256

African (AFR) AF: 0.457 AC: 18905 AN: 41400

American (AMR) AF: 0.196 AC: 2992 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 403 AN: 3466

East Asian (EAS) AF: 0.0907 AC: 468 AN: 5160

South Asian (SAS) AF: 0.180 AC: 869 AN: 4816

European-Finnish (FIN) AF: 0.108 AC: 1144 AN: 10546

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8295 AN: 67972

Other (OTH) AF: 0.198 AC: 417 AN: 2102

Alfa AF: 0.151 Hom.: 7609

Bravo AF: 0.242

TwinsUK AF: 0.132 AC: 488

ALSPAC AF: 0.135 AC: 521

ESP6500AA AF: 0.442 AC: 1947

ESP6500EA AF: 0.128 AC: 1101

ExAC AF: 0.166 AC: 20100

Asia WGS AF: 0.159 AC: 554 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21569298, 19816713) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Benign	0.69
DEOGEN2	Benign	0.0021	T;.;.;.;.;T;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.66	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0052	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.81	.;.;.;.;N;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;N;N
PhyloP100		2.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.8	N;.;.;.;.;.;N;.;N;.;N;N;.;N;.;.;N;N;N;.;N;N;N
REVEL	Benign	0.054
Sift	Benign	1.0	T;.;.;.;.;.;T;.;T;.;T;T;.;T;.;.;T;T;T;.;T;T;T
Sift4G	Benign	0.59	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0070, 0.0040, 0.017	.;.;.;.;.;.;.;.;.;.;.;B;.;B;.;.;B;B;B;.;B;B;B
Vest4		0.053
MPC		0.028
ClinPred		0.014	T
GERP RS		5.2
PromoterAI		0.0012	Neutral
Varity_R		0.10
gMVP		0.15
Mutation Taster		=275/25	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: rs10825269; hg19: chr10-55955610; COSMIC: COSV57285886; COSMIC: COSV57285886;