rs2305209

Variant names:

Variant summary

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

The NM_022124.6(CDH23):c.1449+130T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,603,650 control chromosomes in the GnomAD database, including 21,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1623 hom., cov: 32)

Exomes 𝑓: 0.16 ( 19426 hom. )

Consequence

CDH23
NM_022124.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0380

Publications

14 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 10-71646747-T-C is Benign according to our data. Variant chr10-71646747-T-C is described in ClinVar as Benign. ClinVar VariationId is 45870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	NM_022124.6	MANE Select	c.1449+130T>C		intron	N/A	NP_071407.4
CDH23	NM_052836.4		c.1579T>C	p.Leu527Leu	synonymous	Exon 14 of 14	NP_443068.1
CDH23	NM_001171930.2		c.1449+130T>C		intron	N/A	NP_001165401.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.1449+130T>C		intron	N/A	ENSP00000224721.9
CDH23	ENST00000461841.7	TSL:5	c.1579T>C	p.Leu527Leu	synonymous	Exon 14 of 14	ENSP00000473454.2
CDH23	ENST00000643732.1		n.1415T>C		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21529

AN:

151794

Hom.:

1625

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.188

Gnomad EAS

AF:

0.0671

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.162

GnomAD2 exomes

AF:

0.144

AC:

34637

AN:

241218

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.0901

Gnomad ASJ exome

AF:

0.187

Gnomad EAS exome

AF:

0.0748

Gnomad FIN exome

AF:

0.119

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.161

AC:

233083

AN:

1451738

Hom.:

19426

Cov.:

AF XY:

0.162

AC XY:

116634

AN XY:

720616

show subpopulations

African (AFR)

AF:

0.115

AC:

3789

AN:

33074

American (AMR)

AF:

0.0928

AC:

4083

AN:

43990

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

4733

AN:

25802

East Asian (EAS)

AF:

0.0747

AC:

2949

AN:

39500

South Asian (SAS)

AF:

0.178

AC:

15308

AN:

85956

European-Finnish (FIN)

AF:

0.120

AC:

6329

AN:

52754

Middle Eastern (MID)

AF:

0.175

AC:

1003

AN:

5716

European-Non Finnish (NFE)

AF:

0.168

AC:

185547

AN:

1105106

Other (OTH)

AF:

0.156

AC:

9342

AN:

59840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

12066

24131

36197

48262

60328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6576

13152

19728

26304

32880

<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:

0.142

AC:

21531

AN:

151912

Hom.:

1623

Cov.:

AF XY:

0.140

AC XY:

10407

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.116

AC:

4808

AN:

41422

American (AMR)

AF:

0.126

AC:

1920

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

653

AN:

3466

East Asian (EAS)

AF:

0.0669

AC:

345

AN:

5156

South Asian (SAS)

AF:

0.172

AC:

824

AN:

4800

European-Finnish (FIN)

AF:

0.111

AC:

1174

AN:

10568

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.165

AC:

11192

AN:

67928

Other (OTH)

AF:

0.163

AC:

343

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

941

1882

2824

3765

4706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.156

Hom.:

3858

Bravo

AF:

0.142

Asia WGS

AF:

0.109

AC:

378

AN:

3478

EpiCase

AF:

0.175

EpiControl

AF:

0.177

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Autosomal recessive nonsyndromic hearing loss 12 (1)

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types (1)

not provided (1)

Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

4.1

(source)

DANN

Benign

0.43

PhyloP100

0.038

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over