chr10-54317449-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384140.1(PCDH15):c.706-8C>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 0.693 in 1,612,902 control chromosomes in the GnomAD database, including 395,521 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 Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38563 hom., cov: 31)

Exomes 𝑓: 0.69 ( 356958 hom. )

Consequence

PCDH15
NM_001384140.1 splice_region, intron

Scores

Splicing: ADA: 0.00002108

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.274

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 10-54317449-G-A is Benign according to our data. Variant chr10-54317449-G-A is described in ClinVar as [Benign]. Clinvar id is 46511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54317449-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.706-8C>T		splice_region_variant, intron_variant	Intron 7 of 32	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.706-8C>T		splice_region_variant, intron_variant	Intron 7 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.706-8C>T		splice_region_variant, intron_variant	Intron 7 of 32	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.706-8C>T		splice_region_variant, intron_variant	Intron 7 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.705

AC:

107083

AN:

151820

Hom.:

38522

Cov.:

show subpopulations

Gnomad AFR

AF:

0.748

Gnomad AMI

AF:

0.889

Gnomad AMR

AF:

0.678

Gnomad ASJ

AF:

0.768

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.579

Gnomad FIN

AF:

0.690

Gnomad MID

AF:

0.810

Gnomad NFE

AF:

0.727

Gnomad OTH

AF:

0.728

GnomAD3 exomes

AF:

0.657

AC:

164526

AN:

250538

Hom.:

56660

AF XY:

0.660

AC XY:

89380

AN XY:

135448

show subpopulations

Gnomad AFR exome

AF:

0.749

Gnomad AMR exome

AF:

0.602

Gnomad ASJ exome

AF:

0.751

Gnomad EAS exome

AF:

0.213

Gnomad SAS exome

AF:

0.598

Gnomad FIN exome

AF:

0.700

Gnomad NFE exome

AF:

0.729

Gnomad OTH exome

AF:

0.700

GnomAD4 exome

AF:

0.692

AC:

1011049

AN:

1460964

Hom.:

356958

Cov.:

AF XY:

0.691

AC XY:

502447

AN XY:

726804

show subpopulations

Gnomad4 AFR exome

AF:

0.756

Gnomad4 AMR exome

AF:

0.615

Gnomad4 ASJ exome

AF:

0.753

Gnomad4 EAS exome

AF:

0.190

Gnomad4 SAS exome

AF:

0.597

Gnomad4 FIN exome

AF:

0.696

Gnomad4 NFE exome

AF:

0.716

Gnomad4 OTH exome

AF:

0.692

GnomAD4 genome

AF:

0.705

AC:

107184

AN:

151938

Hom.:

38563

Cov.:

AF XY:

0.698

AC XY:

51822

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.748

Gnomad4 AMR

AF:

0.678

Gnomad4 ASJ

AF:

0.768

Gnomad4 EAS

AF:

0.221

Gnomad4 SAS

AF:

0.580

Gnomad4 FIN

AF:

0.690

Gnomad4 NFE

AF:

0.727

Gnomad4 OTH

AF:

0.725

Alfa

AF:

0.729

Hom.:

16936

Bravo

AF:

0.707

Asia WGS

AF:

0.439

AC:

1528

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

May 17, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inferred frequency = 153/302 (LMM data) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F

Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 23

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.82

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

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