rs554938323

Positions:

chr10-71740922-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022124.6(CDH23):c.4589C>T(p.Pro1530Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,613,946 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 12 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.48

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:

CDH23 (HGNC:):

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006159663).

BP6

Variant 10-71740922-C-T is Benign according to our data. Variant chr10-71740922-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=2}. Variant chr10-71740922-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000599 (876/1461648) while in subpopulation SAS AF= 0.00954 (823/86254). AF 95% confidence interval is 0.009. There are 12 homozygotes in gnomad4_exome. There are 624 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.4589C>T	p.Pro1530Leu	missense_variant	37/70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.4589C>T	p.Pro1530Leu	missense_variant	37/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1
CDH23	ENST00000398792.3 linkuse as main transcript	n.1278C>T		non_coding_transcript_exon_variant	8/9	2

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00130

AC:

324

AN:

249292

Hom.:

AF XY:

0.00166

AC XY:

225

AN XY:

135250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0104

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000599

AC:

876

AN:

1461648

Hom.:

Cov.:

AF XY:

0.000858

AC XY:

624

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00954

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000663

GnomAD4 genome

AF:

0.000269

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00787

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000303

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.00136

AC:

165

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CDH23: BP4, BS2 -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Usher syndrome type 1D

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 25, 2017

p.Pro1530Leu in exon 37 of CDH23: This variant is not expected to have clinical significance because it has been identified in 1% (314/30782) of South Asian chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs554938323). -

Usher syndrome type 1

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-0.095

Eigen_PC

Benign

0.020

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0062

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.8

.;L

PrimateAI

Uncertain

0.50

REVEL

Benign

0.26

Sift4G

Uncertain

0.0030

D;.

Polyphen

0.28

.;B

Vest4

0.19

MutPred

0.41

Loss of glycosylation at S1529 (P = 0.0944);Loss of glycosylation at S1529 (P = 0.0944);

MVP

0.81

ClinPred

0.050

GERP RS

3.8

Varity_R

0.073

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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