rs181255269

Variant names:

• chr10-71694233-C-T
• rs181255269
• NM_022124.6:c.2263C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_022124.6:c.2263C>T in CDH23 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 755 (p.His755Tyr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.008578 (781/91042 alleles, 11 homozygotes) for the South Asian population, which is higher than the ClinGen Hearing Loss CDH23 threshold (≥0.005) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.211, which meets no codes. This variant was reported in 2 individuals with Usher syndrome and one with Retinitis Pigmentosa, though without any evidence of pathogenicity (PM3 not met; PMIDs: 18429043, 21569298, 30718709). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 12/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA137317/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (13 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:2 B:18
• Conservation: PhyloP100: 5.96
• Publications: 18 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
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.2263C>T	p.His755Tyr	missense	Exon 21 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.2263C>T	p.His755Tyr	missense	Exon 21 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.2263C>T	p.His755Tyr	missense	Exon 21 of 26	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2263C>T	p.His755Tyr	missense	Exon 21 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.2263C>T	p.His755Tyr	missense	Exon 21 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.2263C>T	p.His755Tyr	missense	Exon 21 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152060 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00892

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00218 AC: 542 AN: 248490 AF XY: 0.00268

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00657

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.000613

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00145 AC: 2118 AN: 1460878 Hom.: 13 Cov.: 32 AF XY: 0.00171 AC XY: 1246 AN XY: 726652

African (AFR) AF: 0.000179 AC: 6 AN: 33472

American (AMR) AF: 0.000828 AC: 37 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00685 AC: 179 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00856 AC: 738 AN: 86224

European-Finnish (FIN) AF: 0.000622 AC: 33 AN: 53088

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5762

European-Non Finnish (NFE) AF: 0.000839 AC: 933 AN: 1111460

Other (OTH) AF: 0.00212 AC: 128 AN: 60348

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152178 Hom.: 1 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74384

African (AFR) AF: 0.000193 AC: 8 AN: 41520

American (AMR) AF: 0.000523 AC: 8 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4818

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00129 Hom.: 1

Bravo AF: 0.000914

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00130 AC: 11

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00237

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	3	not specified (3)
-	1	1	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types (1)
-	-	1	Non-Syndromic Hereditary Hearing Impairment (1)
-	-	1	Nonsyndromic genetic hearing loss (1)
1	-	-	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)
-	1	-	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0067	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.0
PrimateAI	Uncertain	0.63	T
REVEL	Benign	0.21
Sift4G	Benign	0.11	T
Polyphen		0.95	P
Vest4		0.64
MVP		0.73
ClinPred		0.048	T
GERP RS		5.5
Varity_R		0.50
gMVP		0.54
Mutation Taster		=67/33	polymorphism

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: rs181255269; hg19: chr10-73453990;