rs11818398

chr10-71810577-G-Achr10-71810577-G-T

Variant summary

Our verdict is Benign. Variant got -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:9
• Conservation: PhyloP100: 0.703

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]

LOC124902446 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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. Variant chr10-71810577-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CDH23	NM_022124.6	c.9077+8G>A		splice_region_variant, intron_variant		ENST00000224721.12
LOC124902446	XR_007062185.1	n.1316C>T		non_coding_transcript_exon_variant	2/2
CDH23	NM_001171933.1	c.2357+8G>A		splice_region_variant, intron_variant
CDH23	NM_001171934.1	c.2357+8G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.9077+8G>A		splice_region_variant, intron_variant		5	NM_022124.6	P1

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

GnomAD3 exomes AF: 0.169 AC: 41912 AN: 248730 Hom.: 3815 AF XY: 0.168 AC XY: 22665 AN XY: 134944

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 SAS exome AF: 0.127

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

Gnomad4 AFR exome AF: 0.0761

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.275

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.176

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

Gnomad4 AFR AF: 0.0787

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.156

Alfa AF: 0.168 Hom.: 963

Bravo AF: 0.143

Asia WGS AF: 0.135 AC: 472 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2013	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. -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.7
Dann	Benign	0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs11818398; hg19: chr10-73570334; COSMIC: COSV56452798;