rs79854148

Positions:

• chr10-53822019-T-C

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.5707A>G​(p.Ile1903Val) variant causes a missense change. The variant allele was found at a frequency of 0.00666 in 1,614,002 control chromosomes in the GnomAD database, including 643 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (327 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (316 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.88

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=0.0016710162).
• BP6: Variant 10-53822019-T-C is Benign according to our data. Variant chr10-53822019-T-C is described in ClinVar as [Benign]. Clinvar id is 46507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53822019-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.5707A>G	p.Ile1903Val	missense_variant	33/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4368-1789A>G		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.5707A>G	p.Ile1903Val	missense_variant	33/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.4368-1789A>G		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.0352 AC: 5356 AN: 152148 Hom.: 328 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00954 AC: 2398 AN: 251328 Hom.: 139 AF XY: 0.00720 AC XY: 978 AN XY: 135824

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00368 AC: 5375 AN: 1461736 Hom.: 316 Cov.: 32 AF XY: 0.00322 AC XY: 2343 AN XY: 727170

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00891

GnomAD4 genome AF: 0.0353 AC: 5371 AN: 152266 Hom.: 327 Cov.: 32 AF XY: 0.0342 AC XY: 2547 AN XY: 74462

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00634 Hom.: 92

Bravo AF: 0.0398

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.122 AC: 539

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0120 AC: 1452

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2017	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	Eurofins Ntd Llc (ga)	Mar 20, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 01, 2011	Ile1903Val in exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because has been identified with a frequency of 21% in the West Afri can population (dbSNP rs79854148). In addition, this residue is not conserved in mammals and this variant occurs at an equal frequency in probands (1/113) and c ontrols (1/80) (Ouyang 2005). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1F Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1 Benign:1

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 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	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0095	.;T;.;.;.;.;.;.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;.;.;.;.;.;.;.;M
MutationTaster	Benign	0.0014	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.11	N;.;.;N;N;N;.;N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;.;.;D;D;D;.;D;D
Sift4G	Benign	0.080	T;T;T;T;T;T;T;T;T
Polyphen		0.82	P;.;.;P;P;P;.;P;P
Vest4		0.18
MPC		0.025
ClinPred		0.049	T
GERP RS		5.3
Varity_R		0.18
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: rs79854148; hg19: chr10-55581779;