rs41281304

chr10-71646693-C-Achr10-71646693-C-Gchr10-71646693-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022124.6(CDH23):c.1449+76C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00667 in 1,613,580 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (46 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.211

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049705207).
• BP6: Variant 10-71646693-C-A is Benign according to our data. Variant chr10-71646693-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 45871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71646693-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00506 (771/152278) while in subpopulation NFE AF= 0.00819 (557/68026). AF 95% confidence interval is 0.00763. There are 7 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.1449+76C>A		intron_variant		ENST00000224721.12
CDH23	NM_052836.4	c.1525C>A	p.Pro509Thr	missense_variant	14/14
CDH23	NM_001171930.2	c.1449+76C>A		intron_variant
CDH23	NM_001171931.2	c.1449+76C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.1449+76C>A		intron_variant		5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152160 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00819

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00440 AC: 1090 AN: 247500 Hom.: 3 AF XY: 0.00440 AC XY: 592 AN XY: 134408

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00380

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000789

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00481

GnomAD4 exome AF: 0.00683 AC: 9984 AN: 1461302 Hom.: 46 Cov.: 31 AF XY: 0.00660 AC XY: 4794 AN XY: 726860

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00448

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.000919

Gnomad4 NFE exome AF: 0.00828

Gnomad4 OTH exome AF: 0.00557

GnomAD4 genome AF: 0.00506 AC: 771 AN: 152278 Hom.: 7 Cov.: 33 AF XY: 0.00478 AC XY: 356 AN XY: 74470

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00726

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00819

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00707 Hom.: 7

Bravo AF: 0.00537

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000757 AC: 3

ESP6500EA AF: 0.00674 AC: 56

ExAC AF: 0.00420 AC: 508

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CDH23: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	This variant is associated with the following publications: (PMID: 32707200) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2019	- -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 23, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 30, 2013

Pro509Thr in exon 14 of CDH23: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (56/8306) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs41281304). -

CDH23-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.4
Dann	Benign	0.94
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.069	B;.
Vest4		0.35
MVP		0.25
ClinPred		0.0073	T
GERP RS		0.83

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: rs41281304; hg19: chr10-73406450;