NM_022124.6:c.3230C>T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_022124.6(CDH23):c.3230C>T(p.Pro1077Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 7.88

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 links:

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

C10orf105 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07883695).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000381 (58/152360) while in subpopulation AFR AF= 0.00127 (53/41590). AF 95% confidence interval is 0.001. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.3230C>T	p.Pro1077Leu	missense_variant	Exon 28 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
C10orf105	NM_001164375.3 link	c.*3262G>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000441508.4	NP_001157847.1	Q8TEF2
CDH23	NM_001171930.2 link	c.3230C>T	p.Pro1077Leu	missense_variant	Exon 28 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
C10orf105	NM_001168390.2 link	c.*3262G>A		3_prime_UTR_variant	Exon 2 of 2		NP_001161862.1	Q8TEF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.3230C>T	p.Pro1077Leu	missense_variant	Exon 28 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1
C10orf105	ENST00000441508 link	c.*3262G>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_001164375.3	ENSP00000403151.2		Q8TEF2

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000125

AC:

AN:

248514

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.00156

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461274

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726922

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000381

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000999

Hom.:

Bravo

AF:

0.000476

ESP6500AA

AF:

0.000969

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Apr 28, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Nov 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro1077Leu variant in CDH23 has been identified by our laboratory in one i ndividual with sensorineural hearing loss, who did not carry a second CDH23 vari ant (LMM unpublished data). The variant has been identified in 0.16% (15/9416) o f African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs202101019); however, this frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation a nalysis suggest that this variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro1077Leu variant is uncertain. -

Usher syndrome type 1

Uncertain:1

Mar 03, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinal dystrophy

Uncertain:1

Oct 22, 2018

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.025

T;T;T;T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.079

T;T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.48

.;.;N;.;.

PrimateAI

Uncertain

0.53

REVEL

Benign

0.19

Sift4G

Uncertain

0.0050

D;D;.;D;.

Polyphen

0.28

.;.;B;.;.

Vest4

0.91

MVP

0.80

ClinPred

0.080

GERP RS

4.9

Varity_R

0.37

gMVP

0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over