10-71397124-TGCGAGCG-T

Variant names:

• chr10-71397124-TGCGAGCG-T
• rs527578984
• NM_022124.6:c.-176_-170delGAGCGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_022124.6(CDH23):​c.-176_-170delGAGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 175,598 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: CDH23 NM_022124.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 1.67
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00069 (102/147856) while in subpopulation SAS AF = 0.00177 (8/4526). AF 95% confidence interval is 0.000879. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.-176_-170delGAGCGGC		5_prime_UTR_variant	Exon 1 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.-176_-170delGAGCGGC		5_prime_UTR_variant	Exon 1 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 101 AN: 147726 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000334

Gnomad ASJ AF: 0.00204

Gnomad EAS AF: 0.000210

Gnomad SAS AF: 0.00177

Gnomad FIN AF: 0.000297

Gnomad MID AF: 0.00362

Gnomad NFE AF: 0.000495

Gnomad OTH AF: 0.00195

GnomAD4 exome AF: 0.00115 AC: 32 AN: 27742 Hom.: 1 AF XY: 0.00132 AC XY: 24 AN XY: 18160

African (AFR) AF: 0.00 AC: 0 AN: 168

American (AMR) AF: 0.00 AC: 0 AN: 134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 342

East Asian (EAS) AF: 0.00 AC: 0 AN: 342

South Asian (SAS) AF: 0.00294 AC: 18 AN: 6122

European-Finnish (FIN) AF: 0.000753 AC: 1 AN: 1328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 62

European-Non Finnish (NFE) AF: 0.000658 AC: 12 AN: 18224

Other (OTH) AF: 0.000980 AC: 1 AN: 1020

GnomAD4 genome AF: 0.000690 AC: 102 AN: 147856 Hom.: 0 Cov.: 30 AF XY: 0.000734 AC XY: 53 AN XY: 72206

African (AFR) AF: 0.000996 AC: 40 AN: 40142

American (AMR) AF: 0.000334 AC: 5 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.00204 AC: 7 AN: 3430

East Asian (EAS) AF: 0.000211 AC: 1 AN: 4742

South Asian (SAS) AF: 0.00177 AC: 8 AN: 4526

European-Finnish (FIN) AF: 0.000297 AC: 3 AN: 10092

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.000495 AC: 33 AN: 66728

Other (OTH) AF: 0.00193 AC: 4 AN: 2074

Alfa AF: 0.0000733 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

CDH23-related disorder Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing loss, autosomal recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa-deafness syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=298/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs527578984; hg19: chr10-73156881;