rs80028391

Variant names:

• chr10-71725515-G-A
• rs80028391
• NM_022124.6:c.3574G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.3574G>A​(p.Val1192Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00163 in 1,612,846 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1192G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0091 (29 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (22 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.49
• 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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-71725516-TC-GT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504469.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009121388).
• BP6: Variant 10-71725515-G-A is Benign according to our data. Variant chr10-71725515-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45923.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00912 (1389/152356) while in subpopulation AFR AF = 0.0322 (1337/41576). AF 95% confidence interval is 0.0307. There are 29 homozygotes in GnomAd4. There are 644 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.3574G>A	p.Val1192Ile	missense	Exon 30 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3574G>A	p.Val1192Ile	missense	Exon 30 of 32	NP_001165401.1
	C10orf105	NM_001168390.2		c.-5-9173C>T		intron	N/A	NP_001161862.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3574G>A	p.Val1192Ile	missense	Exon 30 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.3574G>A	p.Val1192Ile	missense	Exon 30 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.3571G>A	p.Val1191Ile	missense	Exon 30 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.00906 AC: 1380 AN: 152238 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00210 AC: 513 AN: 244778 AF XY: 0.00155

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.000790

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.000852 AC: 1245 AN: 1460490 Hom.: 22 Cov.: 32 AF XY: 0.000719 AC XY: 522 AN XY: 726424

African (AFR) AF: 0.0315 AC: 1055 AN: 33448

American (AMR) AF: 0.000965 AC: 43 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111410

Other (OTH) AF: 0.00176 AC: 106 AN: 60310

GnomAD4 genome AF: 0.00912 AC: 1389 AN: 152356 Hom.: 29 Cov.: 33 AF XY: 0.00864 AC XY: 644 AN XY: 74508

African (AFR) AF: 0.0322 AC: 1337 AN: 41576

American (AMR) AF: 0.00196 AC: 30 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68036

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00472 Hom.: 5

Bravo AF: 0.0102

ESP6500AA AF: 0.0297 AC: 118

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00253 AC: 306

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Nov 03, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val1192Ile in exon 30 of CDH23: This variant is not expected to have clinical si gnificance because it has been identified in dbSNP in 4.2% (5/118) West African control chromosomes and 1.2% (11/917) mixed race control chromosomes (rs80028391 ).

Nov 11, 2016

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.

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Usher syndrome type 1 Benign:1

Dec 03, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Usher syndrome type 1D Benign:1

Jan 12, 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:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	0.016
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.5
PrimateAI	Uncertain	0.51	T
REVEL	Benign	0.097
Sift4G	Uncertain	0.023	D
Polyphen		0.14	B
Vest4		0.25
MVP		0.76
ClinPred		0.024	T
GERP RS		3.3
Varity_R		0.022
gMVP		0.20
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs80028391; hg19: chr10-73485272;