rs41281310

chr10-71712737-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022124.6(CDH23):c.3293A>G(p.Asn1098Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,613,678 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (25 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.29

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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01566711).
• BP6: Variant 10-71712737-A-G is Benign according to our data. Variant chr10-71712737-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 45913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71712737-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.3293A>G	p.Asn1098Ser	missense_variant	28/70	ENST00000224721.12
C10orf105	NM_001164375.3	c.*3199T>C		3_prime_UTR_variant	2/2	ENST00000441508.4
CDH23	NM_001171930.2	c.3293A>G	p.Asn1098Ser	missense_variant	28/32
C10orf105	NM_001168390.2	c.*3199T>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3293A>G	p.Asn1098Ser	missense_variant	28/70	5	NM_022124.6	P1
C10orf105	ENST00000441508.4	c.*3199T>C		3_prime_UTR_variant	2/2	1	NM_001164375.3	P1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152244 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00227 AC: 563 AN: 247856 Hom.: 2 AF XY: 0.00234 AC XY: 316 AN XY: 134774

Gnomad AFR exome AF: 0.000975

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.000524

Gnomad FIN exome AF: 0.000558

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00432 AC: 6307 AN: 1461316 Hom.: 25 Cov.: 31 AF XY: 0.00413 AC XY: 3005 AN XY: 726918

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.000640

Gnomad4 NFE exome AF: 0.00530

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00246 AC: 375 AN: 152362 Hom.: 2 Cov.: 33 AF XY: 0.00217 AC XY: 162 AN XY: 74516

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00400

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00366 Hom.: 2

Bravo AF: 0.00276

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00240 AC: 10

ESP6500EA AF: 0.00356 AC: 30

ExAC AF: 0.00232 AC: 281

EpiCase AF: 0.00403

EpiControl AF: 0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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	Feb 01, 2023	CDH23: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21078986, 27068579, 21228398, 18429043, 30245029) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Asn1098Ser in Exon 28 of CDH23: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (24/6836) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41281310). -

CDH23-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 21, 2022

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). -

Usher syndrome type 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 04, 2020

- -

Retinitis pigmentosa-deafness syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;D;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
Sift4G	Pathogenic	0.0	D;D;.;D;.
Polyphen		0.010	.;.;B;.;.
Vest4		0.88
MVP		0.77
ClinPred		0.071	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.67

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: rs41281310; hg19: chr10-73472494;