rs111033467

Variant names:

• chr10-71810494-G-A
• rs111033467
• NM_022124.6:c.9002G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022124.6(CDH23):​c.9002G>A​(p.Arg3001Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000301 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R3001R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.74
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25764483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.9002G>A	p.Arg3001Gln	missense_variant	Exon 62 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.2282G>A	p.Arg761Gln	missense_variant	Exon 15 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.2282G>A	p.Arg761Gln	missense_variant	Exon 15 of 22		NP_001165405.1
LOC124902446	XR_007062185.1	n.1399C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.9002G>A	p.Arg3001Gln	missense_variant	Exon 62 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 249256 AF XY: 0.0000370

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727112

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111838

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Apr 29, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDH23 c.9002G>A (p.Arg3001Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249256 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9002G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Apr 27, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg3001Gln in CDH23 has not been reported in the literature nor previously i dentified by our laboratory in any other families. Computational analyses (bioch emical amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provi de strong support for or against pathogenicity. This variant has now been identi fied in this individual and her sibling, both of whom have sensorineural hearing loss. Although this finding is consistent with a causative role, because two si blings have a 50% chance of sharing any variant by chance, the clinical signific ance of this variant still cannot be determined at this time. -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Uncertain:1

Nov 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Uncertain:1

Oct 28, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3001 of the CDH23 protein (p.Arg3001Gln). This variant is present in population databases (rs111033467, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 46064). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDH23 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.020	T;T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	.;L;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.44	.;.;.;N
REVEL	Benign	0.15
Sift	Benign	0.12	.;.;.;T
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.76	.;P;.;.
Vest4		0.53
MutPred		0.44		Gain of methylation at K2998 (P = 0.0499);Gain of methylation at K2998 (P = 0.0499);.;.;
MVP		0.83
MPC		0.17
ClinPred		0.12	T
GERP RS		5.7
Varity_R		0.35
gMVP		0.53
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111033467; hg19: chr10-73570251; COSMIC: COSV105842246;