rs114137983

chr10-53822312-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_033056.4(PCDH15):c.5414C>T(p.Pro1805Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,609,358 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1805P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (2 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.56

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047721267).
• BP6: Variant 10-53822312-G-A is Benign according to our data. Variant chr10-53822312-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46500.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=1}. Variant chr10-53822312-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00208 (316/152020) while in subpopulation AFR AF= 0.006 (249/41494). AF 95% confidence interval is 0.00539. There are 0 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.5414C>T	p.Pro1805Leu	missense_variant	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-2082C>T		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.5414C>T	p.Pro1805Leu	missense_variant	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-2082C>T		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 317 AN: 151902 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00385

GnomAD3 exomes AF: 0.00107 AC: 255 AN: 238988 Hom.: 0 AF XY: 0.000921 AC XY: 119 AN XY: 129178

Gnomad AFR exome AF: 0.00700

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.000709

Gnomad EAS exome AF: 0.000684

Gnomad SAS exome AF: 0.0000999

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000455

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000581 AC: 847 AN: 1457338 Hom.: 2 Cov.: 32 AF XY: 0.000542 AC XY: 393 AN XY: 724566

Gnomad4 AFR exome AF: 0.00741

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.000460

Gnomad4 EAS exome AF: 0.00126

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.00194 AC XY: 144 AN XY: 74312

Gnomad4 AFR AF: 0.00600

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000777

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.00155 Hom.: 0

Bravo AF: 0.00257

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00636 AC: 28

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000957 AC: 116

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PCDH15: BP4 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro1805Leu in Exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (23/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs114137983). -

Usher syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

PCDH15-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Usher syndrome type 1F Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	6.0
Dann	Benign	0.93
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0048	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.52	N;.;.;N;N;N;.;N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;.;.;D;D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		0.45	B;.;.;B;B;B;.;B;B
Vest4		0.10
MVP		0.74
MPC		0.028
ClinPred		0.053	T
GERP RS		3.5
Varity_R		0.066
gMVP		0.20

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: rs114137983; hg19: chr10-55582072;