rs373838930

Variant names:

• chr10-71791117-G-A
• rs373838930
• NM_022124.6:c.6050-15G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71791117-G-A
• chr10-71791117-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_022124.6(CDH23):​c.6050-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,592,982 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 0.454

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 Uncertain_significance. Variant got 1 ACMG points.

• PP5: Variant 10-71791117-G-A is Pathogenic according to our data. Variant chr10-71791117-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178309.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=2, Likely_pathogenic=2}. Variant chr10-71791117-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.6050-15G>A		intron_variant	Intron 46 of 69	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.6050-15G>A		intron_variant	Intron 46 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000137 AC: 3 AN: 218654 Hom.: 0 AF XY: 0.0000169 AC XY: 2 AN XY: 118686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000364

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 18 AN: 1440882 Hom.: 0 Cov.: 31 AF XY: 0.0000154 AC XY: 11 AN XY: 714894

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000907

Gnomad4 OTH exome AF: 0.0000670

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74292

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.0000655

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: 0.00

Bravo AF: 0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Oct 28, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in loss-of-function (Valero et al, 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31130284, 31546658) -

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 46 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs373838930, gnomAD 0.007%). This variant has been observed in individual(s) with Usher syndrome (PMID: 31546658; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 178309). Studies have shown that this variant results in altered splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 31546658). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Pathogenic:1

Mar 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pituitary adenoma 5, multiple types Pathogenic:1

Dec 22, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Dec 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6050-15G>A variant in CDH23 has not been previously reported in individual s with hearing loss but has been identified in 1/8480 of European chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs 373838930). Although this variant has been seen in the general population, its f requency is not high enough to rule out a pathogenic role. This variant is locat ed in the 3' splice region. Computational tools predict that this variant may cr eate a novel splice acceptor site, which would likely cause a frameshift in the protein; however, this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the c.6050-15G>A variant is unc ertain. -

Usher syndrome type 1D Uncertain:1

Jun 01, 2021

DBGen Ocular Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1

Mar 20, 2018

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 2
DS_AL_spliceai		0.78		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373838930; hg19: chr10-73550874;