rs142857685

chr10-71806270-G-C

Variant summary

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

The NM_022124.6(CDH23):c.8167G>C(p.Val2723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,557,966 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. V2723V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 1.15

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=0.008520603).
• BP6: Variant 10-71806270-G-C is Benign according to our data. Variant chr10-71806270-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46045.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=1}. Variant chr10-71806270-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.8167G>C	p.Val2723Leu	missense_variant	57/70	ENST00000224721.12
CDH23	NM_001171933.1	c.1447G>C	p.Val483Leu	missense_variant	10/23
CDH23	NM_001171934.1	c.1447G>C	p.Val483Leu	missense_variant	10/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.8167G>C	p.Val2723Leu	missense_variant	57/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.000987 AC: 150 AN: 152046 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000297 AC: 49 AN: 165162 Hom.: 0 AF XY: 0.000228 AC XY: 20 AN XY: 87886

Gnomad AFR exome AF: 0.00334

Gnomad AMR exome AF: 0.000313

Gnomad ASJ exome AF: 0.000230

Gnomad EAS exome AF: 0.0000857

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000593

Gnomad OTH exome AF: 0.000867

GnomAD4 exome AF: 0.000176 AC: 248 AN: 1405802 Hom.: 2 Cov.: 31 AF XY: 0.000171 AC XY: 119 AN XY: 694502

Gnomad4 AFR exome AF: 0.00347

Gnomad4 AMR exome AF: 0.000353

Gnomad4 ASJ exome AF: 0.000277

Gnomad4 EAS exome AF: 0.0000549

Gnomad4 SAS exome AF: 0.0000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000544

Gnomad4 OTH exome AF: 0.000753

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152164 Hom.: 3 Cov.: 31 AF XY: 0.00109 AC XY: 81 AN XY: 74388

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000485 Hom.: 1

Bravo AF: 0.00117

ESP6500AA AF: 0.00213 AC: 9

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000217 AC: 25

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 19, 2014	p.Val2723Leu in exon 57 of CDH23: This variant is not expected to have clinical significance because it has been identified in 5.2% (10/192) of LWK (Kenyan) chr omosomes by the 1000 Genomes Project and in 0.2% (9/4222) of African American ch romosomes by the NHLBI Exome Sequencing Project and (http://evs.gs.washington.ed u/EVS/; rs111033480). In addition, the valine (Val) residue at position 2723 is not conserved across species, with at least 3 mammals (David's myotis, big brown bat, microbat) having a leucine (Leu) at this position. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Usher syndrome type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 17, 2020

- -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 30, 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 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 30, 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	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	15
Dann	Benign	0.77
DEOGEN2	Benign	0.0023	T;T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0085	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.74	D;N
PrimateAI	Benign	0.46	T
Sift4G	Benign	1.0	T;.;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.23
MutPred		0.34		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;.;
MVP		0.70
MPC		0.14
ClinPred		0.015	T
GERP RS		3.3
Varity_R		0.041
gMVP		0.23

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: rs142857685; hg19: chr10-73566027;