NM_022124.6:c.2171G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_022124.6(CDH23):c.2171G>A(p.Arg724His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,588,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R724G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 9.41

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029466987).

BP6

Variant 10-71690579-G-A is Benign according to our data. Variant chr10-71690579-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162893.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000723 (11/152172) while in subpopulation SAS AF = 0.00145 (7/4824). AF 95% confidence interval is 0.00068. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.2171G>A	p.Arg724His	missense_variant	Exon 20 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.2171G>A	p.Arg724His	missense_variant	Exon 20 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.2171G>A	p.Arg724His	missense_variant	Exon 20 of 26		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.2171G>A	p.Arg724His	missense_variant	Exon 20 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000296

AC:

AN:

209410

AF XY:

0.000382

show subpopulations

Gnomad AFR exome

AF:

0.0000844

Gnomad AMR exome

AF:

0.0000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.000188

GnomAD4 exome

AF:

0.000160

AC:

230

AN:

1435872

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

154

AN XY:

712048

show subpopulations

African (AFR)

AF:

0.0000608

AC:

AN:

32902

American (AMR)

AF:

0.0000237

AC:

AN:

42264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25566

East Asian (EAS)

AF:

0.00

AC:

AN:

38426

South Asian (SAS)

AF:

0.00179

AC:

147

AN:

81898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000683

AC:

AN:

1097902

Other (OTH)

AF:

0.0000842

AC:

AN:

59400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000723

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41514

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.0000526

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000349

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jul 09, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg724His variant in CDH23 has not been previously reported in individuals w ith hearing loss, but has been identified in 0.03% (1/3864) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs374955091). Although this variant has been seen in the general pop ulation, its frequency is not high enough to rule out a pathogenic role. Computa tional prediction tools and conservation analyses suggest that the Arg724His var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Arg724His variant is uncertain -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.027

T;T;T;.;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.029

T;T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.1

.;.;L;.;.;.

PhyloP100

9.4

PrimateAI

Uncertain

0.72

REVEL

Uncertain

0.29

Sift4G

Uncertain

0.011

D;D;.;D;D;.

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.80

MVP

0.94

ClinPred

0.34

GERP RS

5.1

Varity_R

0.65

gMVP

0.46

Mutation Taster

=57/43

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over