rs780661396

Positions:

• chr10-71677613-G-A
• chr10-71677613-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_022124.6(CDH23):​c.1672G>A​(p.Val558Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,603,260 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a domain Cadherin 5 (size 100) in uniprot entity CAD23_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_022124.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.083800316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1672G>A	p.Val558Met	missense_variant	16/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1672G>A	p.Val558Met	missense_variant	16/32		NP_001165401.1
CDH23	NM_001171931.2	c.1672G>A	p.Val558Met	missense_variant	16/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1672G>A	p.Val558Met	missense_variant	16/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000113 AC: 26 AN: 229490 Hom.: 0 AF XY: 0.000161 AC XY: 20 AN XY: 124122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000363

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000524

GnomAD4 exome AF: 0.000112 AC: 163 AN: 1450978 Hom.: 1 Cov.: 31 AF XY: 0.000112 AC XY: 81 AN XY: 720420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000358

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000867

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74458

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1D Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 558 of the CDH23 protein (p.Val558Met). This variant is present in population databases (rs780661396, gnomAD 0.04%). 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: 228485). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt 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. -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 11, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Val558Met var iant in CDH23 has been previously identified by our laboratory in one individual with hearing loss due to an alternate etiology. This variant has been identifie d in 8/35828 European and 4/10394 South Asian chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs780661396). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. The valine (Val) at position 558 is not conserved in mammals or evolutionarily distant species and 2 mammals (chimpanze e and elephant) carry a methionine (Met), supporting that this change may be tol erated. Additional computational prediction tools suggest that the p.Val558Met variant may not impact the protein, though this information is not predictive en ough to rule out pathogenicity. In summary, while the clinical significance of t he p.Val558Met variant is uncertain, the conservation and computational data sug gest that it is more likely to be benign. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1672G>A (p.V558M) alteration is located in exon 16 (coding exon 15) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 1672, causing the valine (V) at amino acid position 558 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 11, 2020

- -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T;T;T;.;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T;T;T;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.084	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;.;L;.;.;.
PrimateAI	Benign	0.44	T
REVEL	Benign	0.031
Sift4G	Benign	0.33	T;T;.;T;T;.
Polyphen		0.016	.;.;B;.;.;.
Vest4		0.32
MutPred		0.32		Gain of catalytic residue at V554 (P = 0.0994);Gain of catalytic residue at V554 (P = 0.0994);Gain of catalytic residue at V554 (P = 0.0994);Gain of catalytic residue at V554 (P = 0.0994);Gain of catalytic residue at V554 (P = 0.0994);Gain of catalytic residue at V554 (P = 0.0994);
MVP		0.47
ClinPred		0.022	T
GERP RS		2.6
Varity_R		0.065
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs780661396; hg19: chr10-73437370; COSMIC: COSV54935439;