rs727502931

Positions:

• chr10-71799634-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_022124.6(CDH23):​c.7362+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000274 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CDH23 NM_022124.6 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.07

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 10-71799634-G-A is Pathogenic according to our data. Variant chr10-71799634-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71799634-G-A is described in Lovd as [Pathogenic]. Variant chr10-71799634-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.7362+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000224721.12
CDH23	NM_001171933.1	c.642+5G>A		splice_donor_5th_base_variant, intron_variant
CDH23	NM_001171934.1	c.642+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.7362+5G>A		splice_donor_5th_base_variant, intron_variant		5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249264 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461692 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1D Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 21, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -

Pituitary adenoma 5, multiple types Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 29, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

This sequence change falls in intron 52 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 likely results in a shortened protein product. This variant is present in population databases (rs727502931, gnomAD 0.01%). This variant has been observed in individual(s) with Usher syndrome (PMID: 11138009, 11857743, 23591405). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS51+5G>A. ClinVar contains an entry for this variant (Variation ID: 4918). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 52, but is expected to preserve the integrity of the reading-frame (PMID: 11138009). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 25, 2013

The 7362+5G>A variant in CDH23 has been identified in three German individuals w ith Usher syndrome who were either homozygous or had a second variant in CDH23, and was not observed in at least 400 ethnically matched chromosomes (Bolz 2001, von Brederlow 2002, Glockle 2013). In addition, this variant is located in the c onserved 5' splice region, and functional analyses using RT-PCR reveal that the variant causes an in-frame skipping of exon 52 (Bolz 2001). In summary, this var iant meets our criteria to be classified as pathogenic (http://pcpgm.partners.or g/LMM) based upon its presence in individuals with Usher syndrome and its observ ed impact on splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.19		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: rs727502931; hg19: chr10-73559391;