dbSNP rs10823849: CDH23:p.Ala2524Ala (chr10-71802987-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022124.6(CDH23):c.7572G>A(p.Ala2524Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,613,728 control chromosomes in the GnomAD database, including 70,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6163 hom., cov: 32)

Exomes 𝑓: 0.29 ( 64362 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.97

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 10-71802987-G-A is Benign according to our data. Variant chr10-71802987-G-A is described in ClinVar as Benign. ClinVar VariationId is 46034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.514 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.7572G>A	p.Ala2524Ala	synonymous	Exon 54 of 70	NP_071407.4
CDH23	NM_001171933.1		c.852G>A	p.Ala284Ala	synonymous	Exon 7 of 23	NP_001165404.1
CDH23	NM_001171934.1		c.852G>A	p.Ala284Ala	synonymous	Exon 7 of 22	NP_001165405.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.7572G>A	p.Ala2524Ala	synonymous	Exon 54 of 70	ENSP00000224721.9
CDH23	ENST00000475158.1	TSL:1	n.1108G>A		non_coding_transcript_exon	Exon 6 of 21
CDH23	ENST00000642965.1		n.*1415G>A		non_coding_transcript_exon	Exon 9 of 25	ENSP00000495222.1

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41987

AN:

151946

Hom.:

6157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.228

Gnomad AMI

AF:

0.382

Gnomad AMR

AF:

0.330

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.531

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.311

AC:

77390

AN:

249164

AF XY:

0.300

show subpopulations

Gnomad AFR exome

AF:

0.227

Gnomad AMR exome

AF:

0.430

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.527

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.270

Gnomad OTH exome

AF:

0.285

GnomAD4 exome

AF:

0.290

AC:

423505

AN:

1461662

Hom.:

64362

Cov.:

AF XY:

0.286

AC XY:

208009

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.226

AC:

7574

AN:

33480

American (AMR)

AF:

0.418

AC:

18710

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

5844

AN:

26136

East Asian (EAS)

AF:

0.575

AC:

22815

AN:

39700

South Asian (SAS)

AF:

0.247

AC:

21318

AN:

86256

European-Finnish (FIN)

AF:

0.345

AC:

18416

AN:

53390

Middle Eastern (MID)

AF:

0.171

AC:

984

AN:

5768

European-Non Finnish (NFE)

AF:

0.279

AC:

310427

AN:

1111844

Other (OTH)

AF:

0.288

AC:

17417

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

18130

36261

54391

72522

90652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10716

21432

32148

42864

53580

<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:

0.276

AC:

42013

AN:

152066

Hom.:

6163

Cov.:

AF XY:

0.280

AC XY:

20835

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.228

AC:

9466

AN:

41474

American (AMR)

AF:

0.330

AC:

5049

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

771

AN:

3472

East Asian (EAS)

AF:

0.531

AC:

2740

AN:

5160

South Asian (SAS)

AF:

0.263

AC:

1267

AN:

4824

European-Finnish (FIN)

AF:

0.345

AC:

3651

AN:

10570

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.267

AC:

18138

AN:

67968

Other (OTH)

AF:

0.259

AC:

545

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1585

3171

4756

6342

7927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.262

Hom.:

2792

Bravo

AF:

0.278

Asia WGS

AF:

0.358

AC:

1245

AN:

3478

EpiCase

AF:

0.256

EpiControl

AF:

0.258

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Autosomal recessive nonsyndromic hearing loss 12 (1)

Usher syndrome type 1 (1)

Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.055

(source)

DANN

Benign

0.57

PhyloP100

-3.0

Mutation Taster

=92/8

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

Computational scores

Splicing

Publications

Other links and lift over