Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_022124.6(CDH23):c.7467C>T(p.Arg2489Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,613,816 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 59 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 154 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.295

Publications

9 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 10-71800740-C-T is Benign according to our data. Variant chr10-71800740-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.295 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0821 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.7467C>T	p.Arg2489Arg	synonymous	Exon 53 of 70	NP_071407.4
CDH23	NM_001171933.1		c.747C>T	p.Arg249Arg	synonymous	Exon 6 of 23	NP_001165404.1
CDH23	NM_001171934.1		c.747C>T	p.Arg249Arg	synonymous	Exon 6 of 22	NP_001165405.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.7467C>T	p.Arg2489Arg	synonymous	Exon 53 of 70	ENSP00000224721.9
CDH23	ENST00000475158.1	TSL:1	n.1003C>T		non_coding_transcript_exon	Exon 5 of 21
CDH23	ENST00000642965.1		n.*1310C>T		non_coding_transcript_exon	Exon 8 of 25	ENSP00000495222.1

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2694

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.0894

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.00462

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0121

AC:

3016

AN:

249090

AF XY:

0.0106

show subpopulations

Gnomad AFR exome

AF:

0.0431

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.00418

Gnomad EAS exome

AF:

0.0848

Gnomad FIN exome

AF:

0.00311

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.00843

GnomAD4 exome

AF:

0.00471

AC:

6877

AN:

1461606

Hom.:

154

Cov.:

AF XY:

0.00450

AC XY:

3271

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.0431

AC:

1442

AN:

33478

American (AMR)

AF:

0.0134

AC:

598

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00398

AC:

104

AN:

26134

East Asian (EAS)

AF:

0.0720

AC:

2858

AN:

39694

South Asian (SAS)

AF:

0.00568

AC:

490

AN:

86242

European-Finnish (FIN)

AF:

0.00356

AC:

190

AN:

53394

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000515

AC:

573

AN:

1111820

Other (OTH)

AF:

0.0100

AC:

606

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

333

666

999

1332

1665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.0177

AC:

2691

AN:

152210

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1338

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0432

AC:

1793

AN:

41516

American (AMR)

AF:

0.0154

AC:

236

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.0888

AC:

460

AN:

5178

South Asian (SAS)

AF:

0.0104

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00462

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68014

Other (OTH)

AF:

0.0104

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

132

263

395

526

658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00930

Hom.:

Bravo

AF:

0.0200

Asia WGS

AF:

0.0610

AC:

211

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 12 (2)

not specified (2)

Usher syndrome type 1D (2)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

7.2

(source)

DANN

Benign

0.62

PhyloP100

-0.29

Mutation Taster

=77/23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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