10-71798514-G-T

Variant names:

• chr10-71798514-G-T
• rs111033495
• NM_022124.6:c.6990G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.6990G>T​(p.Leu2330Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,912 control chromosomes in the GnomAD database, including 8 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. L2330L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.39
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 10-71798514-G-T is Benign according to our data. Variant chr10-71798514-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46024.
• BP7: Synonymous conserved (PhyloP=2.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0057 (869/152338) while in subpopulation AFR AF = 0.0196 (813/41584). AF 95% confidence interval is 0.0184. There are 5 homozygotes in GnomAd4. There are 415 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.6990G>T	p.Leu2330Leu	synonymous	Exon 50 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.270G>T	p.Leu90Leu	synonymous	Exon 3 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.270G>T	p.Leu90Leu	synonymous	Exon 3 of 22	NP_001165405.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.6990G>T	p.Leu2330Leu	synonymous	Exon 50 of 70	ENSP00000224721.9
	CDH23	ENST00000398788.4	TSL:1	c.270G>T	p.Leu90Leu	synonymous	Exon 3 of 23	ENSP00000381768.3
	CDH23	ENST00000619887.4	TSL:1	c.270G>T	p.Leu90Leu	synonymous	Exon 3 of 22	ENSP00000478374.1

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 862 AN: 152220 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00148 AC: 368 AN: 248676 AF XY: 0.000985

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000528 AC: 771 AN: 1461574 Hom.: 3 Cov.: 32 AF XY: 0.000402 AC XY: 292 AN XY: 727082

African (AFR) AF: 0.0180 AC: 603 AN: 33478

American (AMR) AF: 0.00105 AC: 47 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5758

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111802

Other (OTH) AF: 0.00144 AC: 87 AN: 60362

GnomAD4 genome AF: 0.00570 AC: 869 AN: 152338 Hom.: 5 Cov.: 32 AF XY: 0.00557 AC XY: 415 AN XY: 74498

African (AFR) AF: 0.0196 AC: 813 AN: 41584

American (AMR) AF: 0.00242 AC: 37 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00324 Hom.: 0

Bravo AF: 0.00659

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Jun 25, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu2330Leu in Exon 51 of CDH23: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near the splice site, and has been identified in 1.9% (75/3912) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs111033495).

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 1D Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Usher syndrome type 1 Benign:1

Dec 05, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.6
DANN	Benign	0.66
PhyloP100		2.4
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111033495; hg19: chr10-73558271;