Genetic Variant CDH23:c.-183_-170delGAGCGGCGAGCGGC (chr10-71397124-TGCGAGCGGCGAGCG-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_022124.6(CDH23):c.-183_-170delGAGCGGCGAGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 175,596 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00094 ( 1 hom. )

Consequence

CDH23
NM_022124.6 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.82

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00126 (187/147854) while in subpopulation AFR AF = 0.00376 (151/40138). AF 95% confidence interval is 0.00327. There are 0 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.-183_-170delGAGCGGCGAGCGGC		5_prime_UTR_variant	Exon 1 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.-183_-170delGAGCGGCGAGCGGC		5_prime_UTR_variant	Exon 1 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

182

AN:

147726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000802

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000442

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00725

Gnomad NFE

AF:

0.000270

Gnomad OTH

AF:

0.000975

GnomAD4 exome

AF:

0.000937

AC:

AN:

27742

Hom.:

AF XY:

0.00110

AC XY:

AN XY:

18174

show subpopulations

African (AFR)

AF:

0.0119

AC:

AN:

168

American (AMR)

AF:

0.00758

AC:

AN:

132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

340

East Asian (EAS)

AF:

0.00

AC:

AN:

342

South Asian (SAS)

AF:

0.00245

AC:

AN:

6130

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

1324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

18220

Other (OTH)

AF:

0.00196

AC:

AN:

1022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00126

AC:

187

AN:

147854

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

102

AN XY:

72206

show subpopulations

African (AFR)

AF:

0.00376

AC:

151

AN:

40138

American (AMR)

AF:

0.000801

AC:

AN:

14980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

4742

South Asian (SAS)

AF:

0.000442

AC:

AN:

4526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10094

Middle Eastern (MID)

AF:

0.00769

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.000270

AC:

AN:

66728

Other (OTH)

AF:

0.000964

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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10-71397124-TGCGAGCGGCGAGCGGCGAGCG-TGCGAGCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over