chr10-71439832-A-T

Variant names:

• chr10-71439832-A-T
• rs1298721050
• NM_022124.6:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_022124.6(CDH23):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.16
• Publications: 0 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 60 codons. Genomic position: 71510114. Lost 0.018 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 05, 2025

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.1A>T (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon.The next downstream in-frame methionine is located at codon p.Met60. No other start codon variants, nor missense/in-frame variants before Met60 have been associated with disease. The variant was absent in 172822 control chromosomes. 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.1A>T in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1938116). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Sep 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CDH23 mRNA. The next in-frame methionine is located at codon p.Met60. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH23-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the initiator methionine in CDH23. If translation initiates from the next in-frame methionine, the CDH23 protein would no longer include the region containing the p.Glu44 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with CDH23-related conditions (PMID: 30774966), which suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.0067	T;T;T;.;.;T;.
Eigen	Benign	-0.027
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D
MetaSVM	Benign	-0.66	T
PhyloP100		4.2
PROVEAN	Benign	-0.58	N;.;N;.;N;.;.
REVEL	Uncertain	0.29
Sift	Benign	0.29	T;.;D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.
Polyphen		0.17, 0.26	.;.;B;B;.;.;.
Vest4		0.91
MutPred		0.66		Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);Loss of disorder (P = 0.1516);
MVP		0.78
ClinPred		0.97	D
GERP RS		4.6
PromoterAI		-0.059	Neutral
Varity_R		0.43
gMVP		0.24
Mutation Taster		=7/193	disease causing

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: rs1298721050; hg19: chr10-73199589;