Genetic Variant CDH23:c.8064+1G>C (chr10-71805998-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_022124.6(CDH23):c.8064+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 801,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

CDH23
NM_022124.6 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.01

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.019076006 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7, offset of 16, new splice context is: ccgGTgcga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CDH23	NM_022124.6 link	c.8064+1G>C	splice_donor_variant, intron_variant	Intron 56 of 69	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1 link	c.1344+1G>C	splice_donor_variant, intron_variant	Intron 9 of 22		NP_001165404.1
CDH23	NM_001171934.1 link	c.1344+1G>C	splice_donor_variant, intron_variant	Intron 9 of 21		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.8064+1G>C		splice_donor_variant, intron_variant	Intron 56 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000125

AC:

AN:

801720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

412032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18718

American (AMR)

AF:

0.0000272

AC:

AN:

36800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14852

East Asian (EAS)

AF:

0.00

AC:

AN:

16858

South Asian (SAS)

AF:

0.00

AC:

AN:

74076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3596

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

574712

Other (OTH)

AF:

0.00

AC:

AN:

30890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.95

PhyloP100

8.0

GERP RS

4.4

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.75

Position offset: 15

DS_DL_spliceai

0.98

Position offset: -1

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over