10-71738629-T-C

Variant names:

• chr10-71738629-T-C
• rs12218564
• NM_022124.6:c.4341T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):​c.4341T>C​(p.Asp1447Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,346 control chromosomes in the GnomAD database, including 1,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (155 hom., cov: 33)
  • Exomes 𝑓: 0.010 (1112 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.24

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-71738629-T-C is Benign according to our data. Variant chr10-71738629-T-C is described in ClinVar as [Benign]. Clinvar id is 45945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.4341T>C	p.Asp1447Asp	synonymous_variant	Exon 35 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.4341T>C	p.Asp1447Asp	synonymous_variant	Exon 35 of 70	5	NM_022124.6	ENSP00000224721.9
CDH23	ENST00000398792.3	n.1030T>C		non_coding_transcript_exon_variant	Exon 6 of 9	2

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2537 AN: 152200 Hom.: 153 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0982

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0374 AC: 9300 AN: 248412 Hom.: 836 AF XY: 0.0298 AC XY: 4022 AN XY: 134874

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.000631

Gnomad OTH exome AF: 0.0274

GnomAD4 exome AF: 0.00999 AC: 14596 AN: 1461028 Hom.: 1112 Cov.: 32 AF XY: 0.00890 AC XY: 6472 AN XY: 726792

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.00240

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0167 AC: 2547 AN: 152318 Hom.: 155 Cov.: 33 AF XY: 0.0191 AC XY: 1421 AN XY: 74478

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.0988

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00988 Hom.: 60

Bravo AF: 0.0262

Asia WGS AF: 0.0490 AC: 172 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jul 31, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Oct 08, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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 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:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.63
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs12218564; hg19: chr10-73498386;