rs45522532

chr10-71810458-C-Achr10-71810458-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):c.8980-14C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00883 in 1,613,146 control chromosomes in the GnomAD database, including 97 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 0.0065 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (94 hom.)
• Consequence: CDH23 NM_022124.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.599

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]

LOC124902446 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-71810458-C-A is Benign according to our data. Variant chr10-71810458-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46062.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=5, Uncertain_significance=1}. Variant chr10-71810458-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00645 (983/152308) while in subpopulation NFE AF= 0.00991 (674/68018). AF 95% confidence interval is 0.00929. There are 3 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.8980-14C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000224721.12
LOC124902446	XR_007062185.1	n.1435G>T		non_coding_transcript_exon_variant	2/2
CDH23	NM_001171933.1	c.2260-14C>A		splice_polypyrimidine_tract_variant, intron_variant
CDH23	NM_001171934.1	c.2260-14C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.8980-14C>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 984 AN: 152190 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00991

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00686 AC: 1709 AN: 248944 Hom.: 12 AF XY: 0.00723 AC XY: 977 AN XY: 135154

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00362

Gnomad ASJ exome AF: 0.00974

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.00367

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00908 AC: 13269 AN: 1460838 Hom.: 94 Cov.: 31 AF XY: 0.00902 AC XY: 6556 AN XY: 726734

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.00903

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00480

Gnomad4 FIN exome AF: 0.00463

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00918

GnomAD4 genome AF: 0.00645 AC: 983 AN: 152308 Hom.: 3 Cov.: 32 AF XY: 0.00616 AC XY: 459 AN XY: 74472

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00991

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00887 Hom.: 1

Bravo AF: 0.00673

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	8980-14C>A in Intron 61 of CDH23: This variant is not expected to have clinical significance because it has been identified in 0.9% (59/6704) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs45522532). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 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. -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 1D Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CDH23: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	7.8
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45522532; hg19: chr10-73570215;