rs11000013

Variant names:

• chr10-71811764-G-A
• rs11000013
• NM_022124.6:c.9319+11G>A

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.9319+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,567,044 control chromosomes in the GnomAD database, including 11,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.11 (980 hom., cov: 31)
  • Exomes 𝑓: 0.12 (10355 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.90
• Publications: 7 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

LOC124902446 (HGNC:):

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=-0.77).
• BP6: Variant 10-71811764-G-A is Benign according to our data. Variant chr10-71811764-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 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.9319+11G>A		intron	N/A	NP_071407.4
	CDH23	NM_001171933.1		c.2599+11G>A		intron	N/A	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.2599+11G>A		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.9319+11G>A		intron	N/A	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.2855+11G>A		intron	N/A
	CDH23	ENST00000642965.1		n.*3162+11G>A		intron	N/A	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16458 AN: 152122 Hom.: 980 Cov.: 31

Gnomad AFR AF: 0.0926

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0899

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0944

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.111 AC: 19337 AN: 174348 AF XY: 0.116

Gnomad AFR exome AF: 0.0931

Gnomad AMR exome AF: 0.0668

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.00360

Gnomad FIN exome AF: 0.0956

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.116 AC: 164247 AN: 1414804 Hom.: 10355 Cov.: 34 AF XY: 0.118 AC XY: 82830 AN XY: 699700

African (AFR) AF: 0.0910 AC: 2927 AN: 32154

American (AMR) AF: 0.0692 AC: 2535 AN: 36654

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4719 AN: 25370

East Asian (EAS) AF: 0.00232 AC: 85 AN: 36672

South Asian (SAS) AF: 0.137 AC: 11158 AN: 81474

European-Finnish (FIN) AF: 0.0942 AC: 4689 AN: 49798

Middle Eastern (MID) AF: 0.224 AC: 1273 AN: 5678

European-Non Finnish (NFE) AF: 0.119 AC: 130012 AN: 1088290

Other (OTH) AF: 0.117 AC: 6849 AN: 58714

GnomAD4 genome AF: 0.108 AC: 16457 AN: 152240 Hom.: 980 Cov.: 31 AF XY: 0.107 AC XY: 7954 AN XY: 74426

African (AFR) AF: 0.0924 AC: 3839 AN: 41542

American (AMR) AF: 0.0897 AC: 1373 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 626 AN: 3472

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5184

South Asian (SAS) AF: 0.124 AC: 599 AN: 4826

European-Finnish (FIN) AF: 0.0944 AC: 1001 AN: 10608

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8675 AN: 67988

Other (OTH) AF: 0.119 AC: 251 AN: 2114

Alfa AF: 0.119 Hom.: 358

Bravo AF: 0.105

Asia WGS AF: 0.0510 AC: 179 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	Atypical Gaucher Disease (1)
-	-	1	Combined PSAP deficiency (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	Hearing loss, autosomal recessive (1)
-	-	1	Metachromatic leukodystrophy (1)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.5
DANN	Benign	0.72
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11000013;

hg19: chr10-73571521;