dbSNP rs74608315: CDH23:p.Pro346Pro (chr10-71617297-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022124.6(CDH23):c.1038G>A(p.Pro346Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,950 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 35 hom., cov: 32)

Exomes 𝑓: 0.012 ( 319 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -8.05

Publications

7 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
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Usher syndrome type 1
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 10-71617297-G-A is Benign according to our data. Variant chr10-71617297-G-A is described in ClinVar as Benign. ClinVar VariationId is 44112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-8.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

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.1038G>A	p.Pro346Pro	synonymous	Exon 11 of 70	NP_071407.4
CDH23	NM_001171930.2		c.1038G>A	p.Pro346Pro	synonymous	Exon 11 of 32	NP_001165401.1	A0A087WYR8
CDH23	NM_001171931.2		c.1038G>A	p.Pro346Pro	synonymous	Exon 11 of 26	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.1038G>A	p.Pro346Pro	synonymous	Exon 11 of 70	ENSP00000224721.9	Q9H251-1
CDH23	ENST00000616684.4	TSL:5	c.1038G>A	p.Pro346Pro	synonymous	Exon 11 of 32	ENSP00000482036.2	A0A087WYR8
CDH23	ENST00000398809.9	TSL:5	c.1038G>A	p.Pro346Pro	synonymous	Exon 11 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1671

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.0455

Gnomad EAS

AF:

0.0751

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.00985

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0181

AC:

4506

AN:

249326

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.0182

Gnomad ASJ exome

AF:

0.0473

Gnomad EAS exome

AF:

0.0729

Gnomad FIN exome

AF:

0.000604

Gnomad NFE exome

AF:

0.0107

Gnomad OTH exome

AF:

0.0185

GnomAD4 exome

AF:

0.0119

AC:

17387

AN:

1461696

Hom.:

319

Cov.:

AF XY:

0.0125

AC XY:

9054

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

33480

American (AMR)

AF:

0.0169

AC:

758

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0484

AC:

1266

AN:

26134

East Asian (EAS)

AF:

0.0803

AC:

3188

AN:

39698

South Asian (SAS)

AF:

0.0237

AC:

2045

AN:

86258

European-Finnish (FIN)

AF:

0.000768

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.0685

AC:

395

AN:

5768

European-Non Finnish (NFE)

AF:

0.00776

AC:

8623

AN:

1111866

Other (OTH)

AF:

0.0163

AC:

983

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1081

2161

3242

4322

5403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.0110

AC:

1669

AN:

152254

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

885

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41532

American (AMR)

AF:

0.0139

AC:

212

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0455

AC:

158

AN:

3470

East Asian (EAS)

AF:

0.0751

AC:

389

AN:

5182

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4826

European-Finnish (FIN)

AF:

0.000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00985

AC:

670

AN:

68012

Other (OTH)

AF:

0.0161

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0128

Hom.:

Bravo

AF:

0.0125

Asia WGS

AF:

0.0370

AC:

129

AN:

3478

EpiCase

AF:

0.0151

EpiControl

AF:

0.0130

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Autosomal recessive nonsyndromic hearing loss 12 (1)

Usher syndrome type 1 (1)

Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.16

(source)

DANN

Benign

0.71

PhyloP100

-8.0

PromoterAI

-0.0036

Neutral

(source)

Mutation Taster

=85/15

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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