rs185105210

Positions:

• chr10-71645875-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_022124.6(CDH23):​c.1185C>T​(p.Ser395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,613,460 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.106

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 10-71645875-C-T is Benign according to our data. Variant chr10-71645875-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45863.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.1185C>T	p.Ser395=	synonymous_variant	13/70	ENST00000224721.12
CDH23	NM_001171930.2	c.1185C>T	p.Ser395=	synonymous_variant	13/32
CDH23	NM_001171931.2	c.1185C>T	p.Ser395=	synonymous_variant	13/26
CDH23	NM_052836.4	c.1185C>T	p.Ser395=	synonymous_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.1185C>T	p.Ser395=	synonymous_variant	13/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000173 AC: 43 AN: 248846 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135018

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1461134 Hom.: 2 Cov.: 32 AF XY: 0.000125 AC XY: 91 AN XY: 726730

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74480

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000831

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	CDH23: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2020	This variant is associated with the following publications: (PMID: 18429043) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 07, 2011

p.Ser395Ser in exon 13 of CDH23: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located near a splice junction and has been identified in 0.2% (19/9594) of African chromoso mes by the Exome Aggregation Consortium (http://exac.broadinstitute.org/variant/ ; rs185105210). In addition, this variant is listed as presumed neutral in one publication (Oshima 2008). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs185105210; hg19: chr10-73405632;