rs10762480

Variant names:

• chr10-71778221-C-T
• rs10762480
• NM_022124.6:c.5100C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):​c.5100C>T​(p.Tyr1700Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,522 control chromosomes in the GnomAD database, including 33,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (2975 hom., cov: 31)
  • Exomes 𝑓: 0.20 (30630 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.91
• Publications: 19 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
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: 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

ENSG00000306531 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-71778221-C-T is Benign according to our data. Variant chr10-71778221-C-T is described in ClinVar as Benign. ClinVar VariationId is 45965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

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.5100C>T	p.Tyr1700Tyr	synonymous	Exon 40 of 70	NP_071407.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.5100C>T	p.Tyr1700Tyr	synonymous	Exon 40 of 70	ENSP00000224721.9	Q9H251-1
	ENSG00000306531	ENST00000819235.1		n.158-1156G>A		intron	N/A
	ENSG00000306531	ENST00000819236.1		n.157-1053G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29786 AN: 151806 Hom.: 2972 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.187 AC: 46533 AN: 249136 AF XY: 0.185

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.202 AC: 295842 AN: 1461598 Hom.: 30630 Cov.: 35 AF XY: 0.200 AC XY: 145667 AN XY: 727082

African (AFR) AF: 0.188 AC: 6309 AN: 33472

American (AMR) AF: 0.126 AC: 5644 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4446 AN: 26136

East Asian (EAS) AF: 0.220 AC: 8731 AN: 39698

South Asian (SAS) AF: 0.142 AC: 12264 AN: 86254

European-Finnish (FIN) AF: 0.238 AC: 12726 AN: 53390

Middle Eastern (MID) AF: 0.140 AC: 809 AN: 5764

European-Non Finnish (NFE) AF: 0.210 AC: 233180 AN: 1111796

Other (OTH) AF: 0.194 AC: 11733 AN: 60368

GnomAD4 genome AF: 0.196 AC: 29796 AN: 151924 Hom.: 2975 Cov.: 31 AF XY: 0.196 AC XY: 14558 AN XY: 74220

African (AFR) AF: 0.189 AC: 7845 AN: 41410

American (AMR) AF: 0.158 AC: 2421 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 582 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1037 AN: 5150

South Asian (SAS) AF: 0.145 AC: 696 AN: 4810

European-Finnish (FIN) AF: 0.249 AC: 2623 AN: 10538

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14016 AN: 67952

Other (OTH) AF: 0.186 AC: 393 AN: 2112

Alfa AF: 0.204 Hom.: 1754

Bravo AF: 0.188

Asia WGS AF: 0.156 AC: 541 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.95
DANN	Benign	0.82
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10762480; hg19: chr10-73537978; COSMIC: COSV56463967; COSMIC: COSV56463967;