rs61862390

chr10-53822367-G-Achr10-53822367-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):c.5359C>T(p.Pro1787Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,576,182 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (37 hom., cov: 32)
  • Exomes 𝑓: 0.016 (307 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.06

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=0.0032382607).
• BP6: Variant 10-53822367-G-A is Benign according to our data. Variant chr10-53822367-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53822367-G-A is described in Lovd as [Benign]. Variant chr10-53822367-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0152 (2304/151458) while in subpopulation AMR AF= 0.0216 (327/15138). AF 95% confidence interval is 0.0197. There are 37 homozygotes in gnomad4. There are 1334 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 38 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.5359C>T	p.Pro1787Ser	missense_variant	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-2137C>T		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.5359C>T	p.Pro1787Ser	missense_variant	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-2137C>T		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2307 AN: 151340 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00250

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00585

Gnomad FIN AF: 0.0747

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00673

GnomAD3 exomes AF: 0.0184 AC: 3421 AN: 186126 Hom.: 69 AF XY: 0.0173 AC XY: 1734 AN XY: 99994

Gnomad AFR exome AF: 0.00273

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.00297

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00809

Gnomad FIN exome AF: 0.0727

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0155 AC: 22153 AN: 1424724 Hom.: 307 Cov.: 32 AF XY: 0.0153 AC XY: 10770 AN XY: 705728

Gnomad4 AFR exome AF: 0.00214

Gnomad4 AMR exome AF: 0.0202

Gnomad4 ASJ exome AF: 0.00331

Gnomad4 EAS exome AF: 0.0000806

Gnomad4 SAS exome AF: 0.00838

Gnomad4 FIN exome AF: 0.0688

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0152 AC: 2304 AN: 151458 Hom.: 37 Cov.: 32 AF XY: 0.0180 AC XY: 1334 AN XY: 73970

Gnomad4 AFR AF: 0.00249

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.000391

Gnomad4 SAS AF: 0.00606

Gnomad4 FIN AF: 0.0747

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.00666

Alfa AF: 0.0125 Hom.: 34

Bravo AF: 0.00993

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.0123 AC: 106

ExAC AF: 0.0128 AC: 1525

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 29, 2011	Pro1787Ser in exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because this residue is not highly conserved across species. Of note , rat has a serine at this position. In addition, computational analyses do not suggest a high likelihood of clinical significance and this variant is listed in dbSNP with a heterozygous frequency over 1% (rs61862390). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 1F Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 18, 2014	- -

Usher syndrome type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	9.2
Dann	Benign	0.93
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.13	N;.;.;N;N;N;.;N;N
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D;.;.;D;D;D;.;D;D
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T
Polyphen		0.015	B;.;.;B;B;B;.;B;B
Vest4		0.11
MPC		0.028
ClinPred		0.058	T
GERP RS		1.7
Varity_R		0.060
gMVP		0.17

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: rs61862390; hg19: chr10-55582127; COSMIC: COSV57376028; COSMIC: COSV57376028;