rs369396703

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM3PP3PP4

This summary comes from the ClinGen Evidence Repository: The c.1515-12G>A variant in CDH23 is an intronic variant which is located in intron 15. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009% ( 2/21986) in the African/African American population (PM2_supporting, BS1, and BA1 not met). The results from 3 in silico splicing predictors including MaxEntScan indicate that this variant may affect splicing by disrupting the acceptor splice site (PP3). This variant has been detected in 3 individuals with hearing loss and 2 individuals with Usher syndrome. The individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed in trans (PM3, PP4, SCV000564845.4, SCV000804605.2). In summary, this variant is classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10.18.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5543878/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CDH23
NM_022124.6 intron

Scores

Splicing: ADA: 0.9933

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:6

Conservation

PhyloP100: -0.783

Publications

3 publications found

Variant links:

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

CDH23 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1D
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

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.1515-12G>A	intron_variant	Intron 15 of 69	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.1515-12G>A	intron_variant	Intron 15 of 31		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.1515-12G>A	intron_variant	Intron 15 of 25		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.1515-12G>A		intron_variant	Intron 15 of 69	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000221

AC:

AN:

226432

AF XY:

0.0000164

show subpopulations

Gnomad AFR exome

AF:

0.0000753

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000294

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1438586

Hom.:

Cov.:

AF XY:

0.00000983

AC XY:

AN XY:

712028

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33104

American (AMR)

AF:

0.00

AC:

AN:

42536

Ashkenazi Jewish (ASJ)

AF:

0.000156

AC:

AN:

25592

East Asian (EAS)

AF:

0.00

AC:

AN:

38926

South Asian (SAS)

AF:

0.00

AC:

AN:

82868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1098146

Other (OTH)

AF:

0.0000168

AC:

AN:

59524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41392

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

May 02, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified with a second CDH23 variant in patients with bilateral sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 32467589); Classified as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (ClinVar SCV001245157.1; Oza et al., 2018); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32467589, 37575969, 34997062) -

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 15 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. This variant is present in population databases (rs369396703, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 32467589). ClinVar contains an entry for this variant (Variation ID: 228484). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Pituitary adenoma 5, multiple types

Pathogenic:1

Oct 30, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Jul 15, 2021

INGEBI, INGEBI / CONICET

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Already curated by HL expert panel. The allele frequency of the c.1515-12G>A variant in the CDH23 gene is 0.01% (1/9692) of Ashkenazi Jewish chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). Computational prediction tools and conservation analysis suggest that the c.1515-12G>A variant may impact splicing (PP3). This variant was reported in two patients with Usher syndrome (GeneDx unpublished data SCV000564845.2, Human Genetics Radboudumc unpublished data SCV000804605.2) and one with sloping sensorineural hearing loss (LMM unpublished data SCV000271550.2). The probands with Usher syndrome had a suspected-pathogenic variant in CDH23 with an unknown phase (PM3; SCV000564845.2, SCV000804605.2). In this study, two siblings with non-sydromic hearing loss (high frequencies affected )carried this variant in trans with A366T applying to PP1_Sup. In summary, the clinical significance of this variant is Likely Pathogenic based on the ACMG/AMP and gene-specific hearing loss Expert panel standars and guidelines (PM2_Supporting, PM3, PP3, PP1_Sup) -

not specified

Uncertain:1

Aug 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1515-12G>A variant in CDH23 has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 1/26694 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; rs369396703). Although this variant has been seen in the general popu lation, its frequency is not high enough to rule out a pathogenic role. This var iant is located in the 3' splice region. Computational tools suggest an impact to splicing. However, this information is not predictive enough to determine pat hogenicity. In summary, the clinical significance of the c.1515-12G>A variant is uncertain. -

Usher syndrome

Uncertain:1

Oct 18, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.1515-12G>A variant in CDH23 is an intronic variant which is located in intron 15. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009% ( 2/21986) in the African/African American population (PM2_supporting, BS1, and BA1 not met). The results from 3 in silico splicing predictors including MaxEntScan indicate that this variant may affect splicing by disrupting the acceptor splice site (PP3). This variant has been detected in 3 individuals with hearing loss and 2 individuals with Usher syndrome. The individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed in trans (PM3, PP4, SCV000564845.4, SCV000804605.2). In summary, this variant is classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10.18.2023). -

Usher syndrome type 1

Uncertain:1

Aug 10, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Usher syndrome type 1D

Uncertain:1

Sep 01, 2016

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.47

PhyloP100

-0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

1.0

Position offset: 2

DS_AL_spliceai

0.91

Position offset: 12

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