rs143179070

chr10-71707017-G-Achr10-71707017-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):c.3074G>A(p.Gly1025Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,607,446 control chromosomes in the GnomAD database, including 10 homozygotes. 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 0.0033 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (6 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:10
• Conservation: PhyloP100: 9.96

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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011636496).
• BP6: Variant 10-71707017-G-A is Benign according to our data. Variant chr10-71707017-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45908.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=4, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00335 (510/152364) while in subpopulation AFR AF= 0.0111 (463/41588). AF 95% confidence interval is 0.0103. There are 4 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.3074G>A	p.Gly1025Asp	missense_variant	26/70	ENST00000224721.12
CDH23	NM_001171930.2	c.3074G>A	p.Gly1025Asp	missense_variant	26/32
CDH23	NM_001171931.2	c.3074G>A	p.Gly1025Asp	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3074G>A	p.Gly1025Asp	missense_variant	26/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 508 AN: 152246 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.000927 AC: 219 AN: 236206 Hom.: 1 AF XY: 0.000623 AC XY: 80 AN XY: 128314

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000691

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00134

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000375

Gnomad OTH exome AF: 0.000861

GnomAD4 exome AF: 0.000403 AC: 587 AN: 1455082 Hom.: 6 Cov.: 31 AF XY: 0.000343 AC XY: 248 AN XY: 723134

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.000707

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000507

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000307

Gnomad4 OTH exome AF: 0.000815

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152364 Hom.: 4 Cov.: 33 AF XY: 0.00336 AC XY: 250 AN XY: 74514

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000598 Hom.: 2

Bravo AF: 0.00344

ESP6500AA AF: 0.00971 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000975 AC: 118

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1D Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 01, 2014	Gly1025Asp in Exon 26A of CDH23: This variant is not expected to have clinical s ignificance because it has been identified in 1.0% (42/4324) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143179070). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2022	Variant summary: CDH23 c.3074G>A (p.Gly1025Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 236206 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing Usher Syndrome phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=6, VUS n=2). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CDH23: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	This variant is associated with the following publications: (PMID: 28847902, 26969326) -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	UAEU Genomics Laboratory, United Arab Emirates University	Dec 21, 2021	The missense variant NM_022124.6(CDH23):c.3074G>A (p.Gly1025Asp) has been reported previously in association with Ushersyndrome 1D in homozygous state (PMID:26969326). The p.Gly1025Asp variant is observed in 164/13,980 (1.1731%) alleles from individuals of gnomAD African background in gnomAD which is higher than expected for the disorder. However the causes of hearing loss in the middle Eastern population is not well characterized and therefore this variant cannot be excluded based on high MAF. There is a moderate physicochemical difference between glycine and aspartic acid. The p.Gly1025Asp missense variant is predicted to be damaging by both SIFT and PolyPhen2. For these reasons, this variant has been classified as Uncertain Significance. In this patient this variant is inherited from the Father. The patient carries another variant in the same gene, inherited from the mother. In summary the currently available information is insufficient to determine the clinical significance of this variant. Therefore it has been classified as uncertain significance -
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Childhood onset hearing loss Uncertain:1

Uncertain significance, criteria provided, single submitter

research

National Institute on Deafness and Communication Disorders, National Institutes of Health

Jul 08, 2021

PP3 / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. -

CDH23-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;.;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Uncertain	0.036	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.011	D;D;.;D;D;.
Polyphen		0.88	.;.;P;.;.;.
Vest4		0.85
MVP		0.87
ClinPred		0.031	T
GERP RS		5.3
Varity_R		0.55
gMVP		0.71

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: rs143179070; hg19: chr10-73466774;