10-71732339-C-G

Position:

chr10-71732339-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_022124.6(CDH23):c.4068C>G(p.Thr1356=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,582,674 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1356T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0053 ( 8 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 9 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.103

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 10-71732339-C-G is Benign according to our data. Variant chr10-71732339-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45938.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}. Variant chr10-71732339-C-G is described in Lovd as [Likely_benign]. Variant chr10-71732339-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.103 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00527 (803/152348) while in subpopulation AFR AF= 0.0159 (661/41582). AF 95% confidence interval is 0.0149. There are 8 homozygotes in gnomad4. There are 395 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH23	NM_022124.6 linkuse as main transcript	c.4068C>G	p.Thr1356=	synonymous_variant	32/70	ENST00000224721.12
CDH23	NM_001171930.2 linkuse as main transcript	c.4068C>G	p.Thr1356=	synonymous_variant	32/32
C10orf105	NM_001168390.2 linkuse as main transcript	c.-6+5389G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.4068C>G	p.Thr1356=	synonymous_variant	32/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

804

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00226

AC:

445

AN:

196732

Hom.:

AF XY:

0.00200

AC XY:

212

AN XY:

105762

show subpopulations

Gnomad AFR exome

AF:

0.0188

Gnomad AMR exome

AF:

0.000603

Gnomad ASJ exome

AF:

0.0169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000388

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000542

Gnomad OTH exome

AF:

0.00307

GnomAD4 exome

AF:

0.000989

AC:

1414

AN:

1430326

Hom.:

Cov.:

AF XY:

0.000919

AC XY:

651

AN XY:

708760

show subpopulations

Gnomad4 AFR exome

AF:

0.0156

Gnomad4 AMR exome

AF:

0.000888

Gnomad4 ASJ exome

AF:

0.0151

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000245

Gnomad4 OTH exome

AF:

0.00278

GnomAD4 genome

AF:

0.00527

AC:

803

AN:

152348

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

395

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0159

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00595

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 30, 2013	Thr1356Thr in Exon 32A of CDH23: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 1.3% (55/4114) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs143136329). -

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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2019	- -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain: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. -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.49

DANN

Benign

0.55

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