NM_022124.6:c.9086A>C

Variant names:

• chr10-71811323-A-C
• rs397517365
• NM_022124.6:c.9086A>C

Variant summary

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

The NM_022124.6(CDH23):​c.9086A>C​(p.Gln3029Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q3029Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09
• 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

LOC124902446 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.9086A>C	p.Gln3029Pro	missense	Exon 63 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.2366A>C	p.Gln789Pro	missense	Exon 16 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.2366A>C	p.Gln789Pro	missense	Exon 16 of 22	NP_001165405.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9086A>C	p.Gln3029Pro	missense	Exon 63 of 70	ENSP00000224721.9
	CDH23	ENST00000398788.4	TSL:1	c.2366A>C	p.Gln789Pro	missense	Exon 16 of 23	ENSP00000381768.3
	CDH23	ENST00000619887.4	TSL:1	c.2366A>C	p.Gln789Pro	missense	Exon 16 of 22	ENSP00000478374.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2011

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 Gln3029Pro vari ant in CDH23 has not been reported in the literature nor previously identified b y our laboratory. Computational analyses (biochemical amino acid properties, hom ology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. In the absence of additional information, such as identification of a second CDH23 variant in this individual, control data, segregation studies or functional analysis, the clinical significance of this variant cannot be dete rmined at this time.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.83	P
Vest4		0.92
MutPred		0.56		Gain of sheet (P = 0.0827)
MVP		0.78
MPC		0.42
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.49
gMVP		0.87
Mutation Taster		=39/61	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: rs397517365; hg19: chr10-73571080;