rs41304641

Positions:

chr10-54346487-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001384140.1(PCDH15):c.475-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00923 in 1,613,090 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0093 ( 91 hom. )

Consequence

PCDH15
NM_001384140.1 splice_region, intron

Scores

Splicing: ADA: 0.06887

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.21

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 10-54346487-G-A is Benign according to our data. Variant chr10-54346487-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54346487-G-A is described in Lovd as [Likely_benign]. Variant chr10-54346487-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00804 (1224/152146) while in subpopulation NFE AF= 0.011 (749/67982). AF 95% confidence interval is 0.0104. There are 10 homozygotes in gnomad4. There are 578 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.475-3C>T		splice_region_variant, intron_variant		ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 linkuse as main transcript	c.475-3C>T		splice_region_variant, intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.475-3C>T		splice_region_variant, intron_variant		1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.475-3C>T		splice_region_variant, intron_variant			NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.00805

AC:

1224

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.00851

Gnomad ASJ

AF:

0.0329

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00492

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00831

AC:

2087

AN:

251012

Hom.:

AF XY:

0.00865

AC XY:

1174

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00761

Gnomad ASJ exome

AF:

0.0293

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00399

Gnomad FIN exome

AF:

0.00383

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.00935

AC:

13659

AN:

1460944

Hom.:

Cov.:

AF XY:

0.00934

AC XY:

6787

AN XY:

726796

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00812

Gnomad4 ASJ exome

AF:

0.0315

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00395

Gnomad4 FIN exome

AF:

0.00375

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00830

GnomAD4 genome

AF:

0.00804

AC:

1224

AN:

152146

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

578

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00850

Gnomad4 ASJ

AF:

0.0329

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00291

Gnomad4 FIN

AF:

0.00492

Gnomad4 NFE

AF:

0.0110

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00846

EpiCase

AF:

0.0123

EpiControl

AF:

0.0131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PCDH15: BP4, BS1, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 08, 2011	475-3C>T in intron 5 of PCDH15: This variant has previously been identified as a homozygous variant in combination with another likely pathogenic PCDH15 variant in an individual with a clinical diagnosis of Usher syndrome, and therefore the 475-3C>T variant was classified as a polymorphism (http://www.umd.be/PCDH15/). This variant is also listed in dbSNP; however, frequency data is not available ( rs41304641). This variant has been identified by our laboratory in 5/224 (2%) in dividuals tested, none of whom had congenital profound hearing loss consistent w ith pathogenic variants in PCDH15. The 475-3C>T variant is located in the 5' spl ice region but does not affect the highly conserved +1 and +2 positions. In summ ary, this data suggests that this variant is likely to be benign. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2019	Variant summary: PCDH15 c.475-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 2/4 computational tools predict that the variant impacts normal splicing by creating a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0083 in 251012 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 2.63 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.475-3C>T in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar(after 2014) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Usher syndrome type 1F

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.069

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over