rs146819206

chr10-71798442-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):c.6918G>A(p.Leu2306=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,613,968 control chromosomes in the GnomAD database, including 40 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. L2306L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (40 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 3.23

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-71798442-G-A is Benign according to our data. Variant chr10-71798442-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46022.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=1, Uncertain_significance=1}. Variant chr10-71798442-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00115 (175/152322) while in subpopulation SAS AF= 0.0159 (77/4832). AF 95% confidence interval is 0.0131. There are 0 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 13 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.6918G>A	p.Leu2306=	synonymous_variant	50/70	ENST00000224721.12
CDH23	NM_001171933.1	c.198G>A	p.Leu66=	synonymous_variant	3/23
CDH23	NM_001171934.1	c.198G>A	p.Leu66=	synonymous_variant	3/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.6918G>A	p.Leu2306=	synonymous_variant	50/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00317 AC: 791 AN: 249188 Hom.: 13 AF XY: 0.00402 AC XY: 543 AN XY: 135200

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000956

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00188 AC: 2749 AN: 1461646 Hom.: 40 Cov.: 32 AF XY: 0.00242 AC XY: 1757 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00677

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0188

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000623

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74484

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0159

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.000880

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2015	p.Leu2306Leu in exon 51 of CDH23: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located nea r a splice junction, has been identified in 1.8% (311/16512) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs146819206). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 25, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2019	This variant is associated with the following publications: (PMID: 18429043, 12075507) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2022	- -

Usher syndrome type 1D Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	6.5
Dann	Benign	0.73

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

Other links and lift over

dbSNP: rs146819206; hg19: chr10-73558199;