rs1227051

Variant names:

• chr10-71741799-G-A
• rs1227051
• NM_022124.6:c.4723G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71741799-G-A
• chr10-71741799-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.4723G>A​(p.Ala1575Thr) variant causes a missense change. The variant allele was found at a frequency of 0.771 in 1,611,736 control chromosomes in the GnomAD database, including 481,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1575A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (41484 hom., cov: 33)
  • Exomes 𝑓: 0.78 (439521 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 6.19
• Publications: 54 publications found

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]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.691493E-6).
• BP6: Variant 10-71741799-G-A is Benign according to our data. Variant chr10-71741799-G-A is described in ClinVar as Benign. ClinVar VariationId is 45955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.4723G>A	p.Ala1575Thr	missense	Exon 38 of 70	NP_071407.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4723G>A	p.Ala1575Thr	missense	Exon 38 of 70	ENSP00000224721.9
	CDH23	ENST00000398792.3	TSL:2	n.1412G>A		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111674 AN: 152044 Hom.: 41460 Cov.: 33

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.745

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.786

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.761

GnomAD2 exomes AF: 0.774 AC: 189554 AN: 244850 AF XY: 0.777

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.776

Gnomad ASJ exome AF: 0.850

Gnomad EAS exome AF: 0.832

Gnomad FIN exome AF: 0.746

Gnomad NFE exome AF: 0.782

Gnomad OTH exome AF: 0.789

GnomAD4 exome AF: 0.775 AC: 1131293 AN: 1459574 Hom.: 439521 Cov.: 67 AF XY: 0.776 AC XY: 563594 AN XY: 725860

African (AFR) AF: 0.595 AC: 19911 AN: 33444

American (AMR) AF: 0.770 AC: 34192 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 22222 AN: 26040

East Asian (EAS) AF: 0.824 AC: 32663 AN: 39654

South Asian (SAS) AF: 0.785 AC: 67425 AN: 85900

European-Finnish (FIN) AF: 0.747 AC: 39650 AN: 53060

Middle Eastern (MID) AF: 0.788 AC: 4543 AN: 5766

European-Non Finnish (NFE) AF: 0.778 AC: 864213 AN: 1111002

Other (OTH) AF: 0.771 AC: 46474 AN: 60296

GnomAD4 genome AF: 0.734 AC: 111743 AN: 152162 Hom.: 41484 Cov.: 33 AF XY: 0.734 AC XY: 54617 AN XY: 74380

African (AFR) AF: 0.611 AC: 25378 AN: 41524

American (AMR) AF: 0.769 AC: 11773 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2982 AN: 3470

East Asian (EAS) AF: 0.821 AC: 4231 AN: 5154

South Asian (SAS) AF: 0.788 AC: 3799 AN: 4824

European-Finnish (FIN) AF: 0.747 AC: 7914 AN: 10598

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53163 AN: 67972

Other (OTH) AF: 0.763 AC: 1612 AN: 2112

Alfa AF: 0.774 Hom.: 213320

Bravo AF: 0.734

TwinsUK AF: 0.785 AC: 2909

ALSPAC AF: 0.779 AC: 3004

ESP6500AA AF: 0.634 AC: 2783

ESP6500EA AF: 0.796 AC: 6814

ExAC AF: 0.767 AC: 92912

Asia WGS AF: 0.780 AC: 2712 AN: 3478

EpiCase AF: 0.794

EpiControl AF: 0.790

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inferred frequency = 172/301

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Usher syndrome type 1D Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 1 Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Retinitis pigmentosa-deafness syndrome Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.75
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
PhyloP100		6.2
PrimateAI	Benign	0.42	T
REVEL	Benign	0.10
Sift4G	Benign	1.0	T
Vest4		0.082
ClinPred		0.0096	T
GERP RS		5.1
Varity_R		0.17
gMVP		0.12
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1227051; hg19: chr10-73501556; COSMIC: COSV56490242; COSMIC: COSV56490242;