NM_022124.6:c.204C>T

Variant names:

• chr10-71510140-C-T
• rs116624130
• NM_022124.6:c.204C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_022124.6(CDH23):​c.204C>T​(p.Gly68Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,613,982 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (44 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.88
• Publications: 4 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-AS1 (HGNC:31433): (CDH23 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 10-71510140-C-T is Benign according to our data. Variant chr10-71510140-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1980/152314) while in subpopulation AFR AF = 0.041 (1702/41556). AF 95% confidence interval is 0.0393. There are 39 homozygotes in GnomAd4. There are 997 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

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.204C>T	p.Gly68Gly	synonymous	Exon 4 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.204C>T	p.Gly68Gly	synonymous	Exon 4 of 32	NP_001165401.1
	CDH23	NM_001171931.2		c.204C>T	p.Gly68Gly	synonymous	Exon 4 of 26	NP_001165402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.204C>T	p.Gly68Gly	synonymous	Exon 4 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.204C>T	p.Gly68Gly	synonymous	Exon 4 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.204C>T	p.Gly68Gly	synonymous	Exon 4 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1971 AN: 152196 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00451 AC: 1123 AN: 249276 AF XY: 0.00377

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00219 AC: 3200 AN: 1461668 Hom.: 44 Cov.: 31 AF XY: 0.00205 AC XY: 1493 AN XY: 727114

African (AFR) AF: 0.0422 AC: 1411 AN: 33468

American (AMR) AF: 0.00340 AC: 152 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 470 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000672 AC: 58 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.000687 AC: 764 AN: 1111850

Other (OTH) AF: 0.00518 AC: 313 AN: 60374

GnomAD4 genome AF: 0.0130 AC: 1980 AN: 152314 Hom.: 39 Cov.: 32 AF XY: 0.0134 AC XY: 997 AN XY: 74482

African (AFR) AF: 0.0410 AC: 1702 AN: 41556

American (AMR) AF: 0.00712 AC: 109 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68030

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00948 Hom.: 16

Bravo AF: 0.0148

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Oct 05, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gly68Gly in exon 4 of CDH23: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located near a s plice junction and is listed in dbSNP with a frequency of 9.6% (23/239) control chromosomes (rs116624130).

PreventionGenetics, part of Exact Sciences

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

Usher syndrome type 1D Benign:1

Jan 12, 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:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.6
DANN	Benign	0.80
PhyloP100		-5.9
Mutation Taster		=97/3	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: rs116624130; hg19: chr10-73269897;