Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2

The NM_022124.6(CDH23):c.3574G>A(p.Val1192Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00163 in 1,612,846 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1192G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0091 ( 29 hom., cov: 33)

Exomes 𝑓: 0.00085 ( 22 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 5.49

Publications

7 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 links:

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

C10orf105 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-71725516-TC-GT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504469.

BP4

Computational evidence support a benign effect (MetaRNN=0.009121388).

BP6

Variant 10-71725515-G-A is Benign according to our data. Variant chr10-71725515-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45923.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00912 (1389/152356) while in subpopulation AFR AF = 0.0322 (1337/41576). AF 95% confidence interval is 0.0307. There are 29 homozygotes in GnomAd4. There are 644 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

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.3574G>A	p.Val1192Ile	missense	Exon 30 of 70	NP_071407.4
CDH23	NM_001171930.2		c.3574G>A	p.Val1192Ile	missense	Exon 30 of 32	NP_001165401.1
C10orf105	NM_001168390.2		c.-5-9173C>T		intron	N/A	NP_001161862.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3574G>A	p.Val1192Ile	missense	Exon 30 of 70	ENSP00000224721.9
CDH23	ENST00000616684.4	TSL:5	c.3574G>A	p.Val1192Ile	missense	Exon 30 of 32	ENSP00000482036.2
CDH23	ENST00000398809.9	TSL:5	c.3571G>A	p.Val1191Ile	missense	Exon 30 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes

AF:

0.00906

AC:

1380

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00210

AC:

513

AN:

244778

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.0320

Gnomad AMR exome

AF:

0.000790

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.000503

GnomAD4 exome

AF:

0.000852

AC:

1245

AN:

1460490

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

522

AN XY:

726424

show subpopulations

African (AFR)

AF:

0.0315

AC:

1055

AN:

33448

American (AMR)

AF:

0.000965

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.000128

AC:

AN:

86000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111410

Other (OTH)

AF:

0.00176

AC:

106

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00912

AC:

1389

AN:

152356

Hom.:

Cov.:

AF XY:

0.00864

AC XY:

644

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0322

AC:

1337

AN:

41576

American (AMR)

AF:

0.00196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68036

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00472

Hom.:

Bravo

AF:

0.0102

ESP6500AA

AF:

0.0297

AC:

118

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00253

AC:

306

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000595

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Autosomal recessive nonsyndromic hearing loss 12 (1)

not provided (1)

Usher syndrome type 1 (1)

Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

Eigen

Benign

0.016

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.87

MutationAssessor

Benign

2.0

PhyloP100

5.5

PrimateAI

Uncertain

0.51

REVEL

Benign

0.097

Sift4G

Uncertain

0.023

Polyphen

0.14

Vest4

0.25

MVP

0.76

ClinPred

0.024

GERP RS

3.3

Varity_R

0.022

gMVP

0.20

Mutation Taster

=82/18

polymorphism

(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