10-71741862-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS1_Supporting

The NM_022124.6(CDH23):c.4786C>T(p.Arg1596Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,610,716 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. R1596H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.93

Publications

6 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: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_022124.6

BP4

Computational evidence support a benign effect (MetaRNN=0.25279945).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000425 (62/1458464) while in subpopulation MID AF = 0.00208 (12/5764). AF 95% confidence interval is 0.0012. There are 1 homozygotes in GnomAdExome4. There are 32 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.4786C>T	p.Arg1596Cys	missense_variant	Exon 38 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.4786C>T	p.Arg1596Cys	missense_variant	Exon 38 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1
CDH23	ENST00000398792.3 link	n.1475C>T		non_coding_transcript_exon_variant	Exon 9 of 9	2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.0000291

AC:

AN:

240566

AF XY:

0.00000763

show subpopulations

Gnomad AFR exome

AF:

0.000414

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000566

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000425

AC:

AN:

1458464

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

725250

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52666

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1110774

Other (OTH)

AF:

0.000116

AC:

AN:

60240

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

Exome Hom

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:

0.000131

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000386

AC:

AN:

41466

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000107

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000459

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000413

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:1

Jan 06, 2024

Wonkam Laboratory, Johns Hopkins University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This variant CDH23 c.4786C>T (NM_022124.5) is predicted to lead to a missense mutation that is absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium PM2). The variant segregated with multiple individuals with hearing impairment for a gene known to cause the phenotype being investigated (PP1), patient's phenotype and family history is highly specific for a disease with single origin (PP4). -

not specified

Uncertain:1

Oct 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg1596Cys variant in CDH23 has not been previously reported in individual s with hearing loss, but has been identified in 4/6868 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s372636295). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predi ction tools suggest that the variant may impact the protein, though this informa tion is not predictive enough to assume pathogenicity. In summary, the clinical significance of the p.Arg1596Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

2.0

.;M

PhyloP100

2.9

PrimateAI

Benign

0.23

REVEL

Benign

0.22

Sift4G

Pathogenic

0.0010

D;.

Polyphen

0.99

.;D

Vest4

0.65

MVP

0.77

ClinPred

0.35

GERP RS

5.1

Varity_R

0.13

gMVP

0.51

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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