rs10740579

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033056.4(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_033056.4 splice_region, intron

Scores

Splicing: ADA: 0.00002108

Clinical Significance

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

Conservation

PhyloP100: -0.274

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 23
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 46511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.657

AC:

164526

AN:

250538

AF XY:

0.660

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 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

African (AFR)

AF:

0.756

AC:

25309

AN:

33458

American (AMR)

AF:

0.615

AC:

27492

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.753

AC:

19667

AN:

26116

East Asian (EAS)

AF:

0.190

AC:

7530

AN:

39692

South Asian (SAS)

AF:

0.597

AC:

51523

AN:

86238

European-Finnish (FIN)

AF:

0.696

AC:

37125

AN:

53360

Middle Eastern (MID)

AF:

0.780

AC:

4492

AN:

5760

European-Non Finnish (NFE)

AF:

0.716

AC:

796171

AN:

1111298

Other (OTH)

AF:

0.692

AC:

41740

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

17150

34299

51449

68598

85748

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19638

39276

58914

78552

98190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.705

AC:

107184

AN:

151938

Hom.:

38563

Cov.:

AF XY:

0.698

AC XY:

51822

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.748

AC:

31001

AN:

41436

American (AMR)

AF:

0.678

AC:

10326

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.768

AC:

2661

AN:

3466

East Asian (EAS)

AF:

0.221

AC:

1138

AN:

5138

South Asian (SAS)

AF:

0.580

AC:

2796

AN:

4822

European-Finnish (FIN)

AF:

0.690

AC:

7289

AN:

10560

Middle Eastern (MID)

AF:

0.813

AC:

239

AN:

294

European-Non Finnish (NFE)

AF:

0.727

AC:

49401

AN:

67972

Other (OTH)

AF:

0.725

AC:

1522

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1496

2992

4489

5985

7481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

816

1632

2448

3264

4080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.729

Hom.:

17148

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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) -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

DANN

Benign

0.58

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over