10-71791167-C-T

Variant names:

• chr10-71791167-C-T
• rs750880909
• NM_022124.6:c.6085C>T

Variant summary

Our verdict is Pathogenic. The variant received 4 ACMG points: 4P and 0B. PP3 PP1 PM3

This summary comes from the ClinGen Evidence Repository: The c.6085C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 2029 (p.Arg2029Trp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.02% (3/17816 alleles) in the East Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in many individuals with hearing loss or deafness, without any reported vision loss or evidence of retinopathy. Of those individuals, over 10 were homozygous or compound heterozygous for the variant and a pathogenic or likely pathogenic and many of those were confirmed in trans (6.75 PM3_Very Strong points, PMID:35020051, 25963016, 22899989, 17850630). The variant has been reported to segregate with hearing loss in 1 affected family member from 1 family (PP1_Supporting; PMID:22899989, 17850630). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3, PP1. (VCEP specifications version 2; 06.26.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5545996/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 1.83
• 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: Pathogenic. The variant received 4 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.6085C>T	p.Arg2029Trp	missense	Exon 47 of 70	NP_071407.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.6085C>T	p.Arg2029Trp	missense	Exon 47 of 70	ENSP00000224721.9	Q9H251-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000244 AC: 6 AN: 245426 AF XY: 0.0000375

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1459914 Hom.: 0 Cov.: 31 AF XY: 0.0000317 AC XY: 23 AN XY: 726070

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00116 AC: 46 AN: 39644

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111292

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000453 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
1	-	-	Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types (1)
1	-	-	Nonsyndromic genetic hearing loss (1)
1	-	-	Pituitary adenoma 5, multiple types (1)
1	-	-	Syndromic retinitis pigmentosa (1)
1	-	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.8
PrimateAI	Uncertain	0.54	T
REVEL	Pathogenic	0.70
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.92		Loss of catalytic residue at R2029 (P = 0.1277)
MVP		0.89
ClinPred		0.88	D
GERP RS		5.0
Varity_R		0.60
gMVP		0.80
Mutation Taster		=40/60	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs750880909; hg19: chr10-73550924; COSMIC: COSV56475458; COSMIC: COSV56475458;