rs111033480

chr10-71779391-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_022124.6(CDH23):c.5312G>A(p.Arg1771Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,613,692 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 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 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:8
• Conservation: PhyloP100: 0.804

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021293283).
• BP6: Variant 10-71779391-G-A is Benign according to our data. Variant chr10-71779391-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45974.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Likely_pathogenic=1}. Variant chr10-71779391-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.5312G>A	p.Arg1771Gln	missense_variant	41/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.5312G>A	p.Arg1771Gln	missense_variant	41/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000756 AC: 188 AN: 248600 Hom.: 0 AF XY: 0.000815 AC XY: 110 AN XY: 134922

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.000755

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00275

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000799

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000440 AC: 643 AN: 1461398 Hom.: 5 Cov.: 31 AF XY: 0.000499 AC XY: 363 AN XY: 726952

Gnomad4 AFR exome AF: 0.00496

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000855

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152294 Hom.: 2 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74474

Gnomad4 AFR AF: 0.00450

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.00155

ESP6500AA AF: 0.00201 AC: 8

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.000819 AC: 99

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 19, 2014	p.Arg1771Gln in exon 41 of CDH23: This variant is not expected to have clinical significance because it has been identified in 5.7% (11/192) of LWK (Kenyan) chr omosomes by the 1000 Genomes Project and in 0.2% (8/3976) of African American ch romosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; rs111033480). In addition the arginine (Arg) amino acid at 1771 is not conse rved across species, with over 10 mammals have a glutamine at this position desp ite high nearby amino acid conservation. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2017	- -

Usher syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Dec 31, 2022

- -

Usher syndrome type 1D Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	10
Dann	Benign	0.90
DEOGEN2	Benign	0.0090	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.51	T;.
Polyphen		0.037	.;B
Vest4		0.21
MVP		0.67
ClinPred		0.018	T
GERP RS		-2.5
Varity_R		0.041
gMVP		0.15

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: rs111033480; hg19: chr10-73539148;