NM_022124.6:c.-35_-31delAGGCG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_022124.6(CDH23):c.-35_-31delAGGCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 172,870 control chromosomes in the GnomAD database, including 1,393 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1313 hom., cov: 0)

Exomes 𝑓: 0.067 ( 80 hom. )

Consequence

CDH23
NM_022124.6 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.67

Publications

2 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: Benign. The variant received -16 ACMG points.

BP6

Variant 10-71397276-CCGAGG-C is Benign according to our data. Variant chr10-71397276-CCGAGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 300395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.-35_-31delAGGCG		5_prime_UTR_variant	Exon 1 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.-35_-31delAGGCG		5_prime_UTR_variant	Exon 1 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.109

AC:

16378

AN:

150180

Hom.:

1304

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.0437

Gnomad AMR

AF:

0.0722

Gnomad ASJ

AF:

0.0781

Gnomad EAS

AF:

0.0781

Gnomad SAS

AF:

0.0968

Gnomad FIN

AF:

0.0812

Gnomad MID

AF:

0.0955

Gnomad NFE

AF:

0.0537

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.0528

AC:

AN:

246

AF XY:

0.0493

show subpopulations

Gnomad NFE exome

AF:

0.0513

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0675

AC:

1524

AN:

22584

Hom.:

AF XY:

0.0692

AC XY:

986

AN XY:

14252

show subpopulations

African (AFR)

AF:

0.123

AC:

AN:

154

American (AMR)

AF:

0.0714

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0652

AC:

AN:

322

East Asian (EAS)

AF:

0.0833

AC:

AN:

156

South Asian (SAS)

AF:

0.0917

AC:

582

AN:

6350

European-Finnish (FIN)

AF:

0.0754

AC:

AN:

1274

Middle Eastern (MID)

AF:

0.159

AC:

AN:

516

European-Non Finnish (NFE)

AF:

0.0508

AC:

654

AN:

12876

Other (OTH)

AF:

0.0602

AC:

AN:

880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.109

AC:

16417

AN:

150286

Hom.:

1313

Cov.:

AF XY:

0.109

AC XY:

7987

AN XY:

73344

show subpopulations

African (AFR)

AF:

0.230

AC:

9476

AN:

41168

American (AMR)

AF:

0.0720

AC:

1094

AN:

15194

Ashkenazi Jewish (ASJ)

AF:

0.0781

AC:

270

AN:

3456

East Asian (EAS)

AF:

0.0779

AC:

380

AN:

4876

South Asian (SAS)

AF:

0.0957

AC:

459

AN:

4798

European-Finnish (FIN)

AF:

0.0812

AC:

833

AN:

10256

Middle Eastern (MID)

AF:

0.103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0537

AC:

3614

AN:

67262

Other (OTH)

AF:

0.106

AC:

222

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

642

1284

1927

2569

3211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0250

Hom.:

703

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 12, 2017

GeneDx

Significance:Benign

Review Status:flagged submission

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Outside ROI, common in our data set -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hearing loss, autosomal recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=113/87

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_022124.6:c.-35_-31delAGGCG

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