rs56107171

Positions:

• chr10-71732072-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_022124.6(CDH23):​c.3801C>T​(p.Thr1267=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,984 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1267T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -3.93

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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-71732072-C-T is Benign according to our data. Variant chr10-71732072-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45930.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=2}. Variant chr10-71732072-C-T is described in Lovd as [Benign]. Variant chr10-71732072-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.93 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.3801C>T	p.Thr1267=	synonymous_variant	32/70	ENST00000224721.12
CDH23	NM_001171930.2	c.3801C>T	p.Thr1267=	synonymous_variant	32/32
C10orf105	NM_001168390.2	c.-6+5656G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3801C>T	p.Thr1267=	synonymous_variant	32/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00144 AC: 359 AN: 249244 Hom.: 0 AF XY: 0.00154 AC XY: 208 AN XY: 135218

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00223 AC: 3256 AN: 1461698 Hom.: 5 Cov.: 31 AF XY: 0.00216 AC XY: 1568 AN XY: 727130

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00274

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74462

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00297

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00199

EpiCase AF: 0.00311

EpiControl AF: 0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 03, 2014	Thr1267Thr in Exon 32A of CDH23: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.3% (25/8476) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs56107171), and in 1.2% (3/ 255) of hispanic chromosomes (CLM, IBS, PUR) by the 1000 Genomes Project. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CDH23: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 1D Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.25
DANN	Benign	0.90

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: rs56107171; hg19: chr10-73491829; COSMIC: COSV99823591;