10-71740842-C-T

Position:

• chr10-71740842-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):​c.4509C>T​(p.Gly1503=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,613,720 control chromosomes in the GnomAD database, including 2,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (340 hom., cov: 33)
  • Exomes 𝑓: 0.017 (1759 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.504

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 10-71740842-C-T is Benign according to our data. Variant chr10-71740842-C-T is described in ClinVar as [Benign]. Clinvar id is 45949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71740842-C-T is described in Lovd as [Benign]. Variant chr10-71740842-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.504 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.4509C>T	p.Gly1503=	synonymous_variant	37/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.4509C>T	p.Gly1503=	synonymous_variant	37/70	5	NM_022124.6	ENSP00000224721	P1
CDH23	ENST00000398792.3	n.1198C>T		non_coding_transcript_exon_variant	8/9	2

Frequencies

GnomAD3 genomes AF: 0.0409 AC: 6229 AN: 152188 Hom.: 339 Cov.: 33

Gnomad AFR AF: 0.0727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0487 AC: 12127 AN: 248956 Hom.: 991 AF XY: 0.0406 AC XY: 5492 AN XY: 135154

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.0178

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.0233

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.0373

GnomAD4 exome AF: 0.0169 AC: 24731 AN: 1461414 Hom.: 1759 Cov.: 31 AF XY: 0.0162 AC XY: 11793 AN XY: 727016

Gnomad4 AFR exome AF: 0.0731

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.0248

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.00160

Gnomad4 OTH exome AF: 0.0261

GnomAD4 genome AF: 0.0410 AC: 6243 AN: 152306 Hom.: 340 Cov.: 33 AF XY: 0.0432 AC XY: 3217 AN XY: 74474

Gnomad4 AFR AF: 0.0726

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0145 Hom.: 207

Bravo AF: 0.0530

Asia WGS AF: 0.0870 AC: 304 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00433

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2013	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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.29
CADD	Benign	7.8
DANN	Benign	0.82

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: rs10999978; hg19: chr10-73500599; COSMIC: COSV56467671; COSMIC: COSV56467671;