chr10-71777692-G-A

Variant names:

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.4858G>A(p.Val1620Met) variant causes a missense change. The variant allele was found at a frequency of 0.0144 in 1,611,636 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1620G) has been classified as Uncertain significance. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.011 ( 24 hom., cov: 32)

Exomes 𝑓: 0.015 ( 341 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 5.23

Publications

16 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:

ENSG00000306531 (HGNC:):

ENSG00000306531 links:

Genome browser will be placed here

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=0.0050043464).

BP6

Variant 10-71777692-G-A is Benign according to our data. Variant chr10-71777692-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0115 (1747/152256) while in subpopulation SAS AF = 0.0451 (218/4832). AF 95% confidence interval is 0.0402. There are 24 homozygotes in GnomAd4. There are 895 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.4858G>A	p.Val1620Met	missense	Exon 39 of 70	NP_071407.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4858G>A	p.Val1620Met	missense	Exon 39 of 70	ENSP00000224721.9	Q9H251-1
ENSG00000306531	ENST00000819235.1		n.158-627C>T		intron	N/A
ENSG00000306531	ENST00000819236.1		n.157-524C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1744

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.0683

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0445

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0174

AC:

4236

AN:

243606

AF XY:

0.0195

show subpopulations

Gnomad AFR exome

AF:

0.00204

Gnomad AMR exome

AF:

0.00792

Gnomad ASJ exome

AF:

0.0672

Gnomad EAS exome

AF:

0.000281

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.0214

GnomAD4 exome

AF:

0.0148

AC:

21534

AN:

1459380

Hom.:

341

Cov.:

AF XY:

0.0160

AC XY:

11631

AN XY:

725712

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33428

American (AMR)

AF:

0.00818

AC:

363

AN:

44398

Ashkenazi Jewish (ASJ)

AF:

0.0701

AC:

1824

AN:

26028

East Asian (EAS)

AF:

0.000151

AC:

AN:

39646

South Asian (SAS)

AF:

0.0484

AC:

4150

AN:

85704

European-Finnish (FIN)

AF:

0.0111

AC:

591

AN:

53242

Middle Eastern (MID)

AF:

0.0198

AC:

112

AN:

5666

European-Non Finnish (NFE)

AF:

0.0119

AC:

13246

AN:

1110968

Other (OTH)

AF:

0.0195

AC:

1178

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1187

2373

3560

4746

5933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.0115

AC:

1747

AN:

152256

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

895

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

41538

American (AMR)

AF:

0.00752

AC:

115

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0683

AC:

237

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0451

AC:

218

AN:

4832

European-Finnish (FIN)

AF:

0.0118

AC:

125

AN:

10604

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

916

AN:

68016

Other (OTH)

AF:

0.0151

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

173

259

346

432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0141

Hom.:

105

Bravo

AF:

0.00987

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00191

AC:

ESP6500EA

AF:

0.0150

AC:

126

ExAC

AF:

0.0171

AC:

2071

Asia WGS

AF:

0.0100

AC:

AN:

3478

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 (5)

Autosomal recessive nonsyndromic hearing loss 12 (2)

Usher syndrome type 1D (2)

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types (1)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0050

MetaSVM

Uncertain

0.085

MutationAssessor

Uncertain

2.3

PhyloP100

5.2

PrimateAI

Uncertain

0.64

REVEL

Benign

0.24

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.45

ClinPred

0.012

GERP RS

5.9

Varity_R

0.12

gMVP

0.55

Mutation Taster

=70/30

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over