rs2394839

Variant names:

• chr10-71784881-A-G
• rs2394839
• NM_022124.6:c.5503-10A>G

Variant summary

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

The ENST00000224721.12(CDH23):​c.5503-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,610,694 control chromosomes in the GnomAD database, including 25,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2022 hom., cov: 33)
  • Exomes 𝑓: 0.17 (23486 hom.)
• Consequence: CDH23 ENST00000224721.12 intron
• Scores: Splicing: ADA: 0.00002974
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.143
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 10-71784881-A-G is Benign according to our data. Variant chr10-71784881-A-G is described in ClinVar as Benign. ClinVar VariationId is 45982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000224721.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.5503-10A>G		intron	N/A	NP_071407.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.5503-10A>G		intron	N/A	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22958 AN: 151678 Hom.: 2020 Cov.: 33

Gnomad AFR AF: 0.0693

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.199 AC: 49640 AN: 248912 AF XY: 0.195

Gnomad AFR exome AF: 0.0687

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.174 AC: 253201 AN: 1458898 Hom.: 23486 Cov.: 32 AF XY: 0.174 AC XY: 126403 AN XY: 725900

African (AFR) AF: 0.0661 AC: 2208 AN: 33404

American (AMR) AF: 0.325 AC: 14524 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4633 AN: 26122

East Asian (EAS) AF: 0.307 AC: 12165 AN: 39686

South Asian (SAS) AF: 0.210 AC: 18079 AN: 86190

European-Finnish (FIN) AF: 0.188 AC: 10020 AN: 53388

Middle Eastern (MID) AF: 0.123 AC: 712 AN: 5766

European-Non Finnish (NFE) AF: 0.163 AC: 180326 AN: 1109386

Other (OTH) AF: 0.175 AC: 10534 AN: 60290

GnomAD4 genome AF: 0.151 AC: 22964 AN: 151796 Hom.: 2022 Cov.: 33 AF XY: 0.155 AC XY: 11492 AN XY: 74180

African (AFR) AF: 0.0692 AC: 2864 AN: 41364

American (AMR) AF: 0.215 AC: 3279 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3466

East Asian (EAS) AF: 0.294 AC: 1512 AN: 5150

South Asian (SAS) AF: 0.215 AC: 1033 AN: 4808

European-Finnish (FIN) AF: 0.187 AC: 1966 AN: 10530

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.164 AC: 11124 AN: 67908

Other (OTH) AF: 0.148 AC: 312 AN: 2106

Alfa AF: 0.160 Hom.: 8477

Bravo AF: 0.153

Asia WGS AF: 0.240 AC: 834 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not specified (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	-0.76
CADD	Benign	3.1
DANN	Benign	0.58
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0020
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: rs2394839; hg19: chr10-73544638; COSMIC: COSV56453812;