dbSNP rs41281310: CDH23:p.Asn1098Ser (chr10-71712737-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022124.6(CDH23):c.3293A>G(p.Asn1098Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,613,678 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene CDH23 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0043 ( 25 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 9.29

Publications

8 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

new If you want to explore the variant's impact on the transcript NM_022124.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01566711).

BP6

Variant 10-71712737-A-G is Benign according to our data. Variant chr10-71712737-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00246 (375/152362) while in subpopulation NFE AF = 0.004 (272/68040). AF 95% confidence interval is 0.00361. There are 2 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,Unknown 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	UniProt
CDH23	NM_022124.6	MANE Select	c.3293A>G	p.Asn1098Ser	missense	Exon 28 of 70	NP_071407.4
C10orf105	NM_001164375.3	MANE Select	c.*3199T>C		3_prime_UTR	Exon 2 of 2	NP_001157847.1	Q8TEF2
CDH23	NM_001171930.2		c.3293A>G	p.Asn1098Ser	missense	Exon 28 of 32	NP_001165401.1	A0A087WYR8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3293A>G	p.Asn1098Ser	missense	Exon 28 of 70	ENSP00000224721.9	Q9H251-1
C10orf105	ENST00000441508.4	TSL:1 MANE Select	c.*3199T>C		3_prime_UTR	Exon 2 of 2	ENSP00000403151.2	Q8TEF2
CDH23	ENST00000616684.4	TSL:5	c.3293A>G	p.Asn1098Ser	missense	Exon 28 of 32	ENSP00000482036.2	A0A087WYR8

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

375

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00400

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00227

AC:

563

AN:

247856

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.000975

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00240

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.000558

Gnomad NFE exome

AF:

0.00390

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00432

AC:

6307

AN:

1461316

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

3005

AN XY:

726918

show subpopulations

African (AFR)

AF:

0.000807

AC:

AN:

33478

American (AMR)

AF:

0.00152

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00298

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000499

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.000640

AC:

AN:

53146

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00530

AC:

5896

AN:

1111810

Other (OTH)

AF:

0.00262

AC:

158

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

340

680

1019

1359

1699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<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:

0.00246

AC:

375

AN:

152362

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41580

American (AMR)

AF:

0.00255

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00400

AC:

272

AN:

68040

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00341

Hom.:

Bravo

AF:

0.00276

EpiCase

AF:

0.00403

EpiControl

AF:

0.00439

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

CDH23-related disorder (1)

Retinitis pigmentosa-deafness syndrome (1)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

2.9

PhyloP100

9.3

PrimateAI

Uncertain

0.49

REVEL

Uncertain

0.51

Sift4G

Pathogenic

0.0

Varity_R

0.30

gMVP

0.67

Mutation Taster

=33/67

disease causing

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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