NM_022124.6:c.9077+8G>A

Variant names:

• chr10-71810577-G-A
• rs11818398
• NM_022124.6:c.9077+8G>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.9077+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,612,384 control chromosomes in the GnomAD database, including 27,803 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1978 hom., cov: 31)
  • Exomes 𝑓: 0.18 (25825 hom.)
• Consequence: CDH23 NM_022124.6 splice_region, intron
• Scores: Splicing: ADA: 0.00004291
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.703
• 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

LOC124902446 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-71810577-G-A is Benign according to our data. Variant chr10-71810577-G-A is described in ClinVar as [Benign]. Clinvar id is 46068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.9077+8G>A		splice_region_variant, intron_variant	Intron 62 of 69	ENST00000224721.12	NP_071407.4
LOC124902446	XR_007062185.1	n.1316C>T		non_coding_transcript_exon_variant	Exon 2 of 2
CDH23	NM_001171933.1	c.2357+8G>A		splice_region_variant, intron_variant	Intron 15 of 22		NP_001165404.1
CDH23	NM_001171934.1	c.2357+8G>A		splice_region_variant, intron_variant	Intron 15 of 21		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.9077+8G>A		splice_region_variant, intron_variant	Intron 62 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23149 AN: 152016 Hom.: 1978 Cov.: 31

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.169 AC: 41912 AN: 248730 AF XY: 0.168

Gnomad AFR exome AF: 0.0764

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.185 AC: 269520 AN: 1460250 Hom.: 25825 Cov.: 32 AF XY: 0.183 AC XY: 132584 AN XY: 726452

African (AFR) AF: 0.0761 AC: 2548 AN: 33464

American (AMR) AF: 0.119 AC: 5337 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4451 AN: 26118

East Asian (EAS) AF: 0.275 AC: 10911 AN: 39668

South Asian (SAS) AF: 0.129 AC: 11112 AN: 86230

European-Finnish (FIN) AF: 0.219 AC: 11675 AN: 53374

Middle Eastern (MID) AF: 0.125 AC: 723 AN: 5766

European-Non Finnish (NFE) AF: 0.191 AC: 212131 AN: 1110626

Other (OTH) AF: 0.176 AC: 10632 AN: 60306

GnomAD4 genome AF: 0.152 AC: 23149 AN: 152134 Hom.: 1978 Cov.: 31 AF XY: 0.154 AC XY: 11423 AN XY: 74390

African (AFR) AF: 0.0787 AC: 3268 AN: 41526

American (AMR) AF: 0.145 AC: 2217 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3472

East Asian (EAS) AF: 0.248 AC: 1280 AN: 5158

South Asian (SAS) AF: 0.127 AC: 611 AN: 4820

European-Finnish (FIN) AF: 0.223 AC: 2364 AN: 10610

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12334 AN: 67954

Other (OTH) AF: 0.156 AC: 329 AN: 2106

Alfa AF: 0.167 Hom.: 964

Bravo AF: 0.143

Asia WGS AF: 0.135 AC: 472 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1D Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.7
DANN	Benign	0.46
PhyloP100		0.70
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.0
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: rs11818398; hg19: chr10-73570334; COSMIC: COSV56452798;