dbSNP rs548188123: CDH23:p.Pro2551Thr (chr10-71803066-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022124.6(CDH23):c.7651C>A(p.Pro2551Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,478 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2551A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.30

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.7651C>A	p.Pro2551Thr	missense_variant	Exon 54 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171933.1 link	c.931C>A	p.Pro311Thr	missense_variant	Exon 7 of 23		NP_001165404.1	Q9H251-7
CDH23	NM_001171934.1 link	c.931C>A	p.Pro311Thr	missense_variant	Exon 7 of 22		NP_001165405.1	Q9H251-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.7651C>A	p.Pro2551Thr	missense_variant	Exon 54 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248234

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457478

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724142

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108468

Other (OTH)

AF:

0.00

AC:

AN:

60142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

T;T;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.82

.;L;.;.

PhyloP100

5.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.4

.;.;.;N

REVEL

Benign

0.26

Sift

Benign

0.23

.;.;.;T

Sift4G

Uncertain

0.0040

D;.;T;T

Polyphen

0.85

.;P;.;.

Vest4

0.61

MutPred

0.56

Gain of catalytic residue at P2551 (P = 0.1112);Gain of catalytic residue at P2551 (P = 0.1112);.;.;

MVP

0.91

MPC

0.26

ClinPred

0.71

GERP RS

5.0

Varity_R

0.17

gMVP

0.26

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over