rs111033453

chr10-71732270-G-Achr10-71732270-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_022124.6(CDH23):c.3999G>A(p.Val1333=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,613,534 control chromosomes in the GnomAD database, including 12 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. V1333V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.48

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-71732270-G-A is Benign according to our data. Variant chr10-71732270-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45935.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}. Variant chr10-71732270-G-A is described in Lovd as [Benign]. Variant chr10-71732270-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.3999G>A	p.Val1333=	synonymous_variant	32/70	ENST00000224721.12
CDH23	NM_001171930.2	c.3999G>A	p.Val1333=	synonymous_variant	32/32
C10orf105	NM_001168390.2	c.-6+5458C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3999G>A	p.Val1333=	synonymous_variant	32/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00310 AC: 769 AN: 247904 Hom.: 3 AF XY: 0.00314 AC XY: 422 AN XY: 134562

Gnomad AFR exome AF: 0.000393

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00549

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000855

Gnomad FIN exome AF: 0.00940

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00264 AC: 3861 AN: 1461228 Hom.: 11 Cov.: 31 AF XY: 0.00269 AC XY: 1958 AN XY: 726842

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000847

Gnomad4 FIN exome AF: 0.00907

Gnomad4 NFE exome AF: 0.00257

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74480

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00329 Hom.: 1

Bravo AF: 0.00214

EpiCase AF: 0.00371

EpiControl AF: 0.00333

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2019	This variant is associated with the following publications: (PMID: 18429043, 28027327) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CDH23: BP4, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 06, 2013	Val1333Val 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% (24/8408) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs111033453). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 01, 2016	- -

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 1D Benign:1

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	8.1
Dann	Benign	0.83

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: rs111033453; hg19: chr10-73492027;