10-71784336-C-G

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.5418C>G(p.Asp1806Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00949 in 1,613,886 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D1806D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 43 hom., cov: 33)

Exomes 𝑓: 0.0090 ( 217 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.83

Publications

17 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
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Usher syndrome type 1
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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 (MetaRNN=0.0017141998).

BP6

Variant 10-71784336-C-G is Benign according to our data. Variant chr10-71784336-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0758 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.5418C>G	p.Asp1806Glu	missense	Exon 42 of 70	NP_071407.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.5418C>G	p.Asp1806Glu	missense	Exon 42 of 70	ENSP00000224721.9	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2185

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0258

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.0826

Gnomad SAS

AF:

0.00993

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00645

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0140

AC:

3494

AN:

249132

AF XY:

0.0135

show subpopulations

Gnomad AFR exome

AF:

0.0260

Gnomad AMR exome

AF:

0.00739

Gnomad ASJ exome

AF:

0.00856

Gnomad EAS exome

AF:

0.0918

Gnomad FIN exome

AF:

0.000928

Gnomad NFE exome

AF:

0.00648

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.00899

AC:

13137

AN:

1461582

Hom.:

217

Cov.:

AF XY:

0.00902

AC XY:

6561

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.0276

AC:

925

AN:

33476

American (AMR)

AF:

0.00763

AC:

341

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00934

AC:

244

AN:

26126

East Asian (EAS)

AF:

0.0886

AC:

3515

AN:

39694

South Asian (SAS)

AF:

0.00896

AC:

773

AN:

86250

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.0212

AC:

122

AN:

5766

European-Non Finnish (NFE)

AF:

0.00585

AC:

6506

AN:

1111802

Other (OTH)

AF:

0.0111

AC:

671

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

654

1309

1963

2618

3272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.0143

AC:

2185

AN:

152304

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1094

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0258

AC:

1072

AN:

41552

American (AMR)

AF:

0.00817

AC:

125

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0822

AC:

426

AN:

5180

South Asian (SAS)

AF:

0.00993

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00645

AC:

439

AN:

68018

Other (OTH)

AF:

0.0151

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

100

200

299

399

499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00882

Hom.:

Bravo

AF:

0.0166

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.0240

AC:

ESP6500EA

AF:

0.00758

AC:

ExAC

AF:

0.0144

AC:

1742

EpiCase

AF:

0.00753

EpiControl

AF:

0.00949

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Usher syndrome type 1D (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)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.31

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0056

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.66

PhyloP100

-1.8

PrimateAI

Uncertain

0.49

REVEL

Benign

0.15

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.20

MutPred

0.40

Loss of ubiquitination at K1805 (P = 0.0715)

ClinPred

0.066

GERP RS

-5.3

Varity_R

0.082

gMVP

0.36

Mutation Taster

=76/24

polymorphism (auto)

(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

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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