rs885014

Variant names:

• chr10-71568064-C-T
• rs885014
• NM_022124.6:c.624+1128C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022124.6(CDH23):​c.624+1128C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 152,042 control chromosomes in the GnomAD database, including 16,322 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.43 (16322 hom., cov: 32)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49
• Publications: 6 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

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.624+1128C>T		intron	N/A	NP_071407.4
	CDH23	NM_001171930.2		c.624+1128C>T		intron	N/A	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.624+1128C>T		intron	N/A	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.624+1128C>T		intron	N/A	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.624+1128C>T		intron	N/A	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.624+1128C>T		intron	N/A	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65579 AN: 151924 Hom.: 16278 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.396

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.432 AC: 65682 AN: 152042 Hom.: 16322 Cov.: 32 AF XY: 0.437 AC XY: 32496 AN XY: 74328

African (AFR) AF: 0.676 AC: 28055 AN: 41472

American (AMR) AF: 0.431 AC: 6579 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1187 AN: 3466

East Asian (EAS) AF: 0.638 AC: 3290 AN: 5156

South Asian (SAS) AF: 0.369 AC: 1776 AN: 4810

European-Finnish (FIN) AF: 0.400 AC: 4225 AN: 10570

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19438 AN: 67980

Other (OTH) AF: 0.394 AC: 831 AN: 2110

Alfa AF: 0.343 Hom.: 24935

Bravo AF: 0.447

Asia WGS AF: 0.470 AC: 1631 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.097
DANN	Benign	0.56
PhyloP100		-1.5
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs885014;

hg19: chr10-73327821;