rs201076440

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_022124.6(CDH23):c.8311G>A(p.Gly2771Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,613,678 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

CDH23
NM_022124.6 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11

Conservation

PhyloP100: 9.96

Publications

11 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.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000608 (888/1461404) while in subpopulation NFE AF = 0.000765 (850/1111702). AF 95% confidence interval is 0.000722. There are 1 homozygotes in GnomAdExome4. There are 416 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.8311G>A	p.Gly2771Ser	missense splice_region	Exon 59 of 70	NP_071407.4
CDH23	NM_001171933.1		c.1591G>A	p.Gly531Ser	missense splice_region	Exon 12 of 23	NP_001165404.1
CDH23	NM_001171934.1		c.1591G>A	p.Gly531Ser	missense splice_region	Exon 12 of 22	NP_001165405.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.8311G>A	p.Gly2771Ser	missense splice_region	Exon 59 of 70	ENSP00000224721.9
CDH23	ENST00000475158.1	TSL:1	n.1847G>A		splice_region non_coding_transcript_exon	Exon 11 of 21
CDH23	ENST00000642965.1		n.*2154G>A		splice_region non_coding_transcript_exon	Exon 14 of 25	ENSP00000495222.1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000391

AC:

AN:

247830

AF XY:

0.000364

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000760

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000608

AC:

888

AN:

1461404

Hom.:

Cov.:

AF XY:

0.000572

AC XY:

416

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000151

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000765

AC:

850

AN:

1111702

Other (OTH)

AF:

0.000364

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.000361

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000495

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000594

AC:

ExAC

AF:

0.000479

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Autosomal recessive nonsyndromic hearing loss 12 (1)

Hearing impairment (1)

Intellectual disability (1)

not specified (1)

Usher syndrome type 1 (1)

Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.5

PhyloP100

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.61

Sift

Uncertain

0.0080

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MVP

0.89

MPC

0.62

ClinPred

0.37

GERP RS

5.4

Varity_R

0.67

gMVP

0.84

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.45

Position offset: 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

Computational scores

Splicing

Publications

Other links and lift over