rs3802708

Variant names:

• chr10-71799470-C-T
• rs3802708
• NM_022124.6:c.7225-22C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.7225-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0857 in 1,613,664 control chromosomes in the GnomAD database, including 8,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.084 (839 hom., cov: 33)
  • Exomes 𝑓: 0.086 (7938 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0380
• Publications: 5 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

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-71799470-C-T is Benign according to our data. Variant chr10-71799470-C-T is described in ClinVar as Benign. ClinVar VariationId is 261554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 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.7225-22C>T		intron	N/A	NP_071407.4
	CDH23	NM_001171933.1		c.505-22C>T		intron	N/A	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.505-22C>T		intron	N/A	NP_001165405.1	Q9H251-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.7225-22C>T		intron	N/A	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.761-22C>T		intron	N/A
	CDH23	ENST00000642965.1		n.*1068-22C>T		intron	N/A	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.0842 AC: 12820 AN: 152204 Hom.: 837 Cov.: 33

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0759

GnomAD2 exomes AF: 0.123 AC: 30730 AN: 249172 AF XY: 0.114

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.0523

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0632

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0859 AC: 125536 AN: 1461342 Hom.: 7938 Cov.: 33 AF XY: 0.0848 AC XY: 61628 AN XY: 726974

African (AFR) AF: 0.0451 AC: 1509 AN: 33480

American (AMR) AF: 0.286 AC: 12768 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 1370 AN: 26128

East Asian (EAS) AF: 0.310 AC: 12294 AN: 39696

South Asian (SAS) AF: 0.104 AC: 8942 AN: 86212

European-Finnish (FIN) AF: 0.124 AC: 6599 AN: 53360

Middle Eastern (MID) AF: 0.0266 AC: 152 AN: 5712

European-Non Finnish (NFE) AF: 0.0687 AC: 76361 AN: 1111684

Other (OTH) AF: 0.0918 AC: 5541 AN: 60352

GnomAD4 genome AF: 0.0842 AC: 12828 AN: 152322 Hom.: 839 Cov.: 33 AF XY: 0.0889 AC XY: 6619 AN XY: 74486

African (AFR) AF: 0.0474 AC: 1971 AN: 41594

American (AMR) AF: 0.164 AC: 2503 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3472

East Asian (EAS) AF: 0.290 AC: 1501 AN: 5172

South Asian (SAS) AF: 0.120 AC: 578 AN: 4834

European-Finnish (FIN) AF: 0.123 AC: 1307 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0655 AC: 4452 AN: 68016

Other (OTH) AF: 0.0761 AC: 161 AN: 2116

Alfa AF: 0.0688 Hom.: 87

Bravo AF: 0.0912

Asia WGS AF: 0.208 AC: 722 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.9
DANN	Benign	0.86
PhyloP100		-0.038
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3802708; hg19: chr10-73559227; COSMIC: COSV56453712;