rs10825269

chr10-54195850-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:10 O:1
• Conservation: PhyloP100: 2.78

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 -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 [Likely_benign]. Clinvar id is 46436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54195850-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PCDH15	NM_033056.4	c.1138G>A	p.Gly380Ser	missense_variant	11/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.1138G>A	p.Gly380Ser	missense_variant	11/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.1138G>A	p.Gly380Ser	missense_variant	11/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.1138G>A	p.Gly380Ser	missense_variant	11/38		NM_001384140.1

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

GnomAD3 exomes AF: 0.162 AC: 40803 AN: 251322 Hom.: 4357 AF XY: 0.156 AC XY: 21203 AN XY: 135844

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 SAS exome AF: 0.183

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

Gnomad4 AFR exome AF: 0.470

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.0668

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.153

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

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0907

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.198

Alfa AF: 0.142 Hom.: 4832

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:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 21569298, 19816713) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Usher syndrome type 1F Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 13, 2022

- -

Usher syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
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
Varity_R		0.10
gMVP		0.15

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: rs10825269; hg19: chr10-55955610; COSMIC: COSV57285886; COSMIC: COSV57285886;