rs397517316

chr10-71695403-CT-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_022124.6(CDH23):c.2290-13del 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 0.00112 in 1,588,278 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0061 (9 hom., cov: 34)
  • Exomes 𝑓: 0.00060 (4 hom.)
• Consequence: CDH23 NM_022124.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.0920

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 10-71695403-CT-C is Benign according to our data. Variant chr10-71695403-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45892.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=3}. Variant chr10-71695403-CT-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00609 (928/152364) while in subpopulation AFR AF= 0.0214 (889/41586). AF 95% confidence interval is 0.0202. There are 9 homozygotes in gnomad4. There are 417 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.2290-13del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000224721.12
CDH23	NM_001171930.2	c.2290-13del		splice_polypyrimidine_tract_variant, intron_variant
CDH23	NM_001171931.2	c.2290-13del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.2290-13del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 925 AN: 152246 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00164 AC: 409 AN: 248956 Hom.: 3 AF XY: 0.00124 AC XY: 167 AN XY: 135120

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000596 AC: 856 AN: 1435914 Hom.: 4 Cov.: 27 AF XY: 0.000494 AC XY: 354 AN XY: 716062

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000368

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00609 AC: 928 AN: 152364 Hom.: 9 Cov.: 34 AF XY: 0.00560 AC XY: 417 AN XY: 74506

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00360 Hom.: 2

Bravo AF: 0.00754

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2019	- -

CDH23-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Nonsyndromic Hearing Loss, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa-deafness syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 02, 2014

2290-13delT in intron 21 of CDH23: This variant is not expected to have clinical significance because it has been identified in 2.32% (90/3876) of African Ameri can chromosomes by the NHLBI Exome Sequencing Project and 2.5% (9/490) of Africa n and African American (ASW, LWK, YRI) chromosomes by the 1000 Genomes Project ( http://evs.gs.washington.edu/EVS/; dbSNP 202233569). In addition, a deletion of a T nucleotide at this position does not diverge from the splice consensus sequ ence and is therefore unlikely to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517316; hg19: chr10-73455160;