rs727502935

Positions:

• chr10-71811591-G-GT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_022124.6(CDH23):​c.9278+2dup variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH23 NM_022124.6 splice_donor
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.007848982 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of -15, new splice context is: ctgGTacta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.9278+2dup		splice_donor_variant		ENST00000224721.12	NP_071407.4
LOC124902446	XR_007062185.1	n.1167_1168insA		non_coding_transcript_exon_variant	1/2
CDH23	NM_001171933.1	c.2558+2dup		splice_donor_variant			NP_001165404.1
CDH23	NM_001171934.1	c.2558+2dup		splice_donor_variant			NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.9278+2dup		splice_donor_variant		5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461654 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2013

Variant classified as Uncertain Significance - Favor Pathogenic. The 9278+2_9278 +3insT variant in CDH23 has not been reported in individuals with hearing loss o r in large population studies. This variant occurs in the 5? splice site and cau ses a divergence from the splice consensus sequence. In addition, computational tools predict altered splicing leading to an abnormal or absent protein. However , additional data is needed to confirm the impact of this variant on the normal splicing of the CDH23 gene. In summary, the clinical significance of this varian t cannot be determined with certainty; however, based upon the change to the spl ice consensus sequence caused by this variant and the computational predictions, we lean towards a more likely pathogenic role. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -16
DS_DL_spliceai		0.94		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs727502935; hg19: chr10-73571348;