rs45583140

chr10-71812008-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):c.9373T>C(p.Phe3125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0501 in 1,612,768 control chromosomes in the GnomAD database, including 3,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F3125S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.045 (328 hom., cov: 33)
  • Exomes 𝑓: 0.051 (3442 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 5.75

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]

LOC124902446 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020181537).
• BP6: Variant 10-71812008-T-C is Benign according to our data. Variant chr10-71812008-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 46072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71812008-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.9373T>C	p.Phe3125Leu	missense_variant	66/70	ENST00000224721.12
LOC124902446	XR_007062185.1	n.751A>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.9373T>C	p.Phe3125Leu	missense_variant	66/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6853 AN: 151384 Hom.: 328 Cov.: 33

Gnomad AFR AF: 0.00978

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0726

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.0917

Gnomad FIN AF: 0.0943

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0421

GnomAD3 exomes AF: 0.0739 AC: 18420 AN: 249186 Hom.: 1180 AF XY: 0.0702 AC XY: 9496 AN XY: 135202

Gnomad AFR exome AF: 0.00949

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.251

Gnomad SAS exome AF: 0.0795

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.0358

Gnomad OTH exome AF: 0.0574

GnomAD4 exome AF: 0.0506 AC: 73952 AN: 1461266 Hom.: 3442 Cov.: 48 AF XY: 0.0506 AC XY: 36816 AN XY: 726924

Gnomad4 AFR exome AF: 0.00720

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.0469

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.0769

Gnomad4 FIN exome AF: 0.0898

Gnomad4 NFE exome AF: 0.0367

Gnomad4 OTH exome AF: 0.0587

GnomAD4 genome AF: 0.0452 AC: 6852 AN: 151502 Hom.: 328 Cov.: 33 AF XY: 0.0501 AC XY: 3710 AN XY: 74014

Gnomad4 AFR AF: 0.00975

Gnomad4 AMR AF: 0.0725

Gnomad4 ASJ AF: 0.0464

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.0920

Gnomad4 FIN AF: 0.0943

Gnomad4 NFE AF: 0.0351

Gnomad4 OTH AF: 0.0427

Alfa AF: 0.0403 Hom.: 399

Bravo AF: 0.0444

TwinsUK AF: 0.0383 AC: 142

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.0106 AC: 42

ESP6500EA AF: 0.0326 AC: 271

ExAC AF: 0.0696 AC: 8411

Asia WGS AF: 0.167 AC: 580 AN: 3478

EpiCase AF: 0.0346

EpiControl AF: 0.0324

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis pigmentosa-deafness syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Atypical Gaucher Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Nonsyndromic Hearing Loss, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Combined PSAP deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Galactosylceramide beta-galactosidase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Metachromatic leukodystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.013	T;T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.9e-9	P;P
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.011	D;.;D;D
Polyphen		0.90	.;P;.;.
Vest4		0.66
MutPred		0.60		Loss of stability (P = 0.1003);Loss of stability (P = 0.1003);.;.;
MPC		0.17
ClinPred		0.015	T
GERP RS		5.8
Varity_R		0.45
gMVP		0.68

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: rs45583140; hg19: chr10-73571765; COSMIC: COSV56453736; COSMIC: COSV56453736;