rs876657760

Variant names:

• chr10-71811717-A-G
• rs876657760
• NM_022124.6:c.9283A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022124.6(CDH23):​c.9283A>G​(p.Lys3095Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.34
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34526807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.9283A>G	p.Lys3095Glu	missense_variant	Exon 65 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.9283A>G	p.Lys3095Glu	missense_variant	Exon 65 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453098 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722212

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 42564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 85412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107858

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 19, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Lys3095Glu va riant in CDH23 has not been previously reported in individuals with hearing loss and data from large population studies is insufficient to assess the frequency of this variant in the general population. Lysine (Lys) at position 3095 is not well conserved in evolutionarily distant species, with 5 fish species having a g lutamic acid (Glu) at this position. Additional computational prediction tools d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Lys3095Glu variant is uncertain, the conser vation data suggests that it is more likely to be benign. -

Usher syndrome type 1 Uncertain:1

Aug 30, 2021

Natera, Inc.

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	0.26
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0095	T;T;.;.
Eigen	Benign	0.058
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	.;L;.;.
PhyloP100		5.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.96	.;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.043	.;.;.;D
Sift4G	Uncertain	0.0070	D;.;D;D
Polyphen		0.022	.;B;.;.
Vest4		0.34
MutPred		0.42		Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);.;.;
MVP		0.80
MPC		0.25
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.39
gMVP		0.60
Mutation Taster		=60/40	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: rs876657760; hg19: chr10-73571474;