rs397517316

Variant names:

• chr10-71695403-CT-C
• rs397517316
• NM_022124.6:c.2290-13delT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_022124.6(CDH23):​c.2290-13delT variant causes a 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 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.0920
• Publications: 0 publications found

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]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 45892.
• 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.2290-13delT		intron	N/A	NP_071407.4
	CDH23	NM_001171930.2		c.2290-13delT		intron	N/A	NP_001165401.1
	CDH23	NM_001171931.2		c.2290-13delT		intron	N/A	NP_001165402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2290-14delT		intron	N/A	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.2290-14delT		intron	N/A	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.2290-14delT		intron	N/A	ENSP00000381789.5

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

GnomAD2 exomes AF: 0.00164 AC: 409 AN: 248956 AF XY: 0.00124

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 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

African (AFR) AF: 0.0201 AC: 666 AN: 33094

American (AMR) AF: 0.00145 AC: 65 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5698

European-Non Finnish (NFE) AF: 0.0000368 AC: 40 AN: 1088224

Other (OTH) AF: 0.00124 AC: 74 AN: 59546

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

African (AFR) AF: 0.0214 AC: 889 AN: 41586

American (AMR) AF: 0.00189 AC: 29 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00360 Hom.: 2

Bravo AF: 0.00754

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	CDH23-related disorder (1)
-	1	-	Hearing loss, autosomal recessive (1)
-	-	1	not specified (1)
-	1	-	Retinitis pigmentosa-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.092
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs397517316; hg19: chr10-73455160;