rs1227065

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.4051A>G(p.Asn1351Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,599,966 control chromosomes in the GnomAD database, including 521,105 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1351N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.80 ( 48634 hom., cov: 33)

Exomes 𝑓: 0.81 ( 472471 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.75

Publications

46 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1604471E-6).

BP6

Variant 10-71732322-A-G is Benign according to our data. Variant chr10-71732322-A-G is described in ClinVar as Benign. ClinVar VariationId is 45937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.4051A>G	p.Asn1351Asp	missense_variant	Exon 32 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.4051A>G	p.Asn1351Asp	missense_variant	Exon 32 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
C10orf105	NM_001168390.2 link	c.-6+5406T>C		intron_variant	Intron 1 of 1		NP_001161862.1	Q8TEF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.4051A>G	p.Asn1351Asp	missense_variant	Exon 32 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.800

AC:

121582

AN:

152062

Hom.:

48603

Cov.:

show subpopulations

Gnomad AFR

AF:

0.777

Gnomad AMI

AF:

0.813

Gnomad AMR

AF:

0.799

Gnomad ASJ

AF:

0.864

Gnomad EAS

AF:

0.832

Gnomad SAS

AF:

0.800

Gnomad FIN

AF:

0.754

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.815

Gnomad OTH

AF:

0.805

GnomAD2 exomes

AF:

0.807

AC:

183095

AN:

226914

AF XY:

0.808

show subpopulations

Gnomad AFR exome

AF:

0.767

Gnomad AMR exome

AF:

0.794

Gnomad ASJ exome

AF:

0.856

Gnomad EAS exome

AF:

0.846

Gnomad FIN exome

AF:

0.756

Gnomad NFE exome

AF:

0.817

Gnomad OTH exome

AF:

0.816

GnomAD4 exome

AF:

0.808

AC:

1169142

AN:

1447786

Hom.:

472471

Cov.:

AF XY:

0.808

AC XY:

580806

AN XY:

718984

show subpopulations

African (AFR)

AF:

0.763

AC:

25282

AN:

33154

American (AMR)

AF:

0.789

AC:

33439

AN:

42398

Ashkenazi Jewish (ASJ)

AF:

0.858

AC:

22191

AN:

25870

East Asian (EAS)

AF:

0.831

AC:

32400

AN:

38976

South Asian (SAS)

AF:

0.800

AC:

67403

AN:

84304

European-Finnish (FIN)

AF:

0.757

AC:

39699

AN:

52442

Middle Eastern (MID)

AF:

0.824

AC:

4744

AN:

5754

European-Non Finnish (NFE)

AF:

0.811

AC:

895602

AN:

1104964

Other (OTH)

AF:

0.807

AC:

48382

AN:

59924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

14851

29702

44554

59405

74256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20782

41564

62346

83128

103910

<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:

0.799

AC:

121662

AN:

152180

Hom.:

48634

Cov.:

AF XY:

0.797

AC XY:

59265

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.776

AC:

32220

AN:

41494

American (AMR)

AF:

0.799

AC:

12222

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.864

AC:

3001

AN:

3472

East Asian (EAS)

AF:

0.832

AC:

4311

AN:

5182

South Asian (SAS)

AF:

0.801

AC:

3857

AN:

4816

European-Finnish (FIN)

AF:

0.754

AC:

7990

AN:

10594

Middle Eastern (MID)

AF:

0.755

AC:

222

AN:

294

European-Non Finnish (NFE)

AF:

0.815

AC:

55394

AN:

68006

Other (OTH)

AF:

0.807

AC:

1705

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1257

2514

3772

5029

6286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

876

1752

2628

3504

4380

<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:

0.815

Hom.:

244392

Bravo

AF:

0.803

TwinsUK

AF:

0.816

AC:

3027

ALSPAC

AF:

0.812

AC:

3128

ESP6500AA

AF:

0.791

AC:

3275

ESP6500EA

AF:

0.824

AC:

6922

ExAC

AF:

0.794

AC:

95662

Asia WGS

AF:

0.798

AC:

2775

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inferred frequency = 196/301 -

Sep 20, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Usher syndrome type 1D

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.0038

T;T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.22

T;T;T;T

MetaRNN

Benign

0.0000012

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.61

.;.;N;.

PhyloP100

7.8

PrimateAI

Uncertain

0.52

REVEL

Benign

0.15

Sift4G

Benign

1.0

T;T;.;T

Vest4

0.20

ClinPred

0.022

GERP RS

5.0

Varity_R

0.42

gMVP

0.22

Mutation Taster

=79/21

polymorphism (auto)

(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