rs202223952

Positions:

chr10-54527887-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_033056.4(PCDH15):c.92-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,604,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00008739

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.110

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 10-54527887-G-A is Benign according to our data. Variant chr10-54527887-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54527887-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
PCDH15	NM_001384140.1 linkuse as main transcript	c.92-10C>T	splice_polypyrimidine_tract_variant, intron_variant	ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4 linkuse as main transcript	c.92-10C>T	splice_polypyrimidine_tract_variant, intron_variant	ENST00000320301.11	NP_149045.3
LOC105378311	NR_134503.1 linkuse as main transcript	n.88-40678G>A	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.92-10C>T	splice_polypyrimidine_tract_variant, intron_variant	1	NM_033056.4	ENSP00000322604	Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.92-10C>T	splice_polypyrimidine_tract_variant, intron_variant		NM_001384140.1	ENSP00000495195
	ENST00000422842.1 linkuse as main transcript	n.88-40678G>A	intron_variant, non_coding_transcript_variant	1

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250774

Hom.:

AF XY:

0.0000811

AC XY:

AN XY:

135580

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

157

AN:

1452454

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

723084

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000140

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.0000756

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 15, 2016	c.92-10C>T in intron 2 of PCDH15: This variant is not expected to have clinical significance because a C>T change at this position does not diverge from the spl ice consensus sequence and is therefore unlikely to impact splicing. It has been identified in 8/66556 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202223952). -

PCDH15-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000087

dbscSNV1_RF

Benign

0.0

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

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