chr10-71807741-G-A

Variant names:

Variant summary

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

The NM_022124.6(CDH23):c.8534G>A(p.Arg2845His) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,606,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2845C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 6.66

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: Uncertain_significance. The variant received 0 ACMG points.

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.8534G>A	p.Arg2845His	missense	Exon 59 of 70	NP_071407.4
CDH23	NM_001171933.1		c.1814G>A	p.Arg605His	missense	Exon 12 of 23	NP_001165404.1
CDH23	NM_001171934.1		c.1814G>A	p.Arg605His	missense	Exon 12 of 22	NP_001165405.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.8534G>A	p.Arg2845His	missense	Exon 59 of 70	ENSP00000224721.9
CDH23	ENST00000398788.4	TSL:1	c.1814G>A	p.Arg605His	missense	Exon 12 of 23	ENSP00000381768.3
CDH23	ENST00000619887.4	TSL:1	c.1814G>A	p.Arg605His	missense	Exon 12 of 22	ENSP00000478374.1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000341

AC:

AN:

234582

AF XY:

0.0000236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000305

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000566

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000115

AC:

167

AN:

1454038

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

722626

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33250

American (AMR)

AF:

0.00

AC:

AN:

43500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.00

AC:

AN:

39262

South Asian (SAS)

AF:

0.0000471

AC:

AN:

84948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52854

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000136

AC:

151

AN:

1108392

Other (OTH)

AF:

0.000183

AC:

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.0000788

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000135

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hearing impairment (1)

Inborn genetic diseases (1)

not specified (1)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.030

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.72

PhyloP100

6.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.3

REVEL

Benign

0.14

Sift

Benign

0.048

Sift4G

Uncertain

0.0030

Polyphen

0.97

Vest4

0.56

MutPred

0.42

Loss of sheet (P = 0.0315)

MVP

0.86

MPC

0.67

ClinPred

0.64

GERP RS

5.6

Varity_R

0.15

gMVP

0.51

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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