rs372401651

Variant names:

• chr10-71705103-A-G
• rs372401651
• NM_022124.6:c.2926A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_022124.6(CDH23):​c.2926A>G​(p.Ser976Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,611,008 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 9.29

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3046442).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000164 (240/1459074) while in subpopulation MID AF= 0.00146 (8/5482). AF 95% confidence interval is 0.000726. There are 2 homozygotes in gnomad4_exome. There are 121 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.2926A>G	p.Ser976Gly	missense_variant	Exon 25 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.2926A>G	p.Ser976Gly	missense_variant	Exon 25 of 32		NP_001165401.1
CDH23	NM_001171931.2	c.2926A>G	p.Ser976Gly	missense_variant	Exon 25 of 26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.2926A>G	p.Ser976Gly	missense_variant	Exon 25 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151814 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000218 AC: 53 AN: 243060 Hom.: 0 AF XY: 0.000270 AC XY: 36 AN XY: 133272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000351

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000164 AC: 240 AN: 1459074 Hom.: 2 Cov.: 32 AF XY: 0.000167 AC XY: 121 AN XY: 725716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0000769

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151934 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74282

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000232 AC: 28

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Jun 15, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533) -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 976 of the CDH23 protein (p.Ser976Gly). This variant is present in population databases (rs372401651, gnomAD 0.03%). This missense change has been observed in individual(s) with inherited retinal disorders (PMID: 38927702). ClinVar contains an entry for this variant (Variation ID: 504554). 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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Uncertain:1

Dec 08, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser976Gly variant in CDH23 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 21/62086 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs372401651). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Com putational prediction tools and conservation analyses do not provide strong supp ort for or against an impact to the protein. In summary, the clinical significan ce of the p.Ser976Gly variant is uncertain. -

Inborn genetic diseases Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2926A>G (p.S976G) alteration is located in exon 25 (coding exon 24) of the CDH23 gene. This alteration results from a A to G substitution at nucleotide position 2926, causing the serine (S) at amino acid position 976 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Usher syndrome type 1D Uncertain:1

Jul 14, 2021

Genome-Nilou Lab

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

- -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1

Jan 01, 2023

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;.;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.;.
PrimateAI	Benign	0.38	T
REVEL	Uncertain	0.40
Sift4G	Uncertain	0.0060	D;D;.;D;D;.
Polyphen		0.36	.;.;B;.;.;.
Vest4		0.52
MVP		0.82
ClinPred		0.64	D
GERP RS		5.5
Varity_R		0.34
gMVP		0.38

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: rs372401651; hg19: chr10-73464860;