rs369013539

Variant names:

• chr10-71677699-G-A
• rs369013539
• NM_022124.6:c.1752+6G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_022124.6(CDH23):​c.1752+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,550,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: CDH23 NM_022124.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001918
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.263

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000512 (78/152298) while in subpopulation AFR AF= 0.00183 (76/41542). AF 95% confidence interval is 0.0015. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1752+6G>A		splice_region_variant, intron_variant	Intron 16 of 69	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1752+6G>A		splice_region_variant, intron_variant	Intron 16 of 31		NP_001165401.1
CDH23	NM_001171931.2	c.1752+6G>A		splice_region_variant, intron_variant	Intron 16 of 25		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1752+6G>A		splice_region_variant, intron_variant	Intron 16 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000137 AC: 22 AN: 160338 Hom.: 0 AF XY: 0.0000942 AC XY: 8 AN XY: 84956

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.0000802

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000436

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000158

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000636 AC: 89 AN: 1398478 Hom.: 0 Cov.: 30 AF XY: 0.0000565 AC XY: 39 AN XY: 690360

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.000111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.000172

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74468

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000349 Hom.: 0

Bravo AF: 0.000710

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Oct 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 16 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369013539, gnomAD 0.2%). This variant has been observed in individual(s) with CDH23-related conditions (PMID: 22135276). ClinVar contains an entry for this variant (Variation ID: 228486). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jun 19, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.1752+6G>A var iant in CDH23 has been previously reported in 1 individual with Usher syndrome; however, it was classified as likely benign by the authors of the study based on either the presence of two other pathogenic/likely pathogenic variants in the i ndividual or nonsegregation of the variant with disease (Le Quesne 2012). It has also been identified in 0.2% (5/2316) of African chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369013539); how ever this frequency is not high enough to rule out a pathogenic role. This varia nt is located in the 5' splice region. Computational tools do not suggest an imp act to the nascent 5' splice site, though this information is not predictive eno ugh to rule out pathogenicity. In summary, while the clinical significance of th e c.1752+6G>A variant is uncertain, these data suggest it is more likely to be b enign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0
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: rs369013539; hg19: chr10-73437456;