rs763582705

Positions:

• chr10-71785707-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_022124.6(CDH23):​c.5789A>G​(p.Asp1930Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1930N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.27

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.5789A>G	p.Asp1930Gly	missense_variant	44/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.5789A>G	p.Asp1930Gly	missense_variant	44/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000418 AC: 1 AN: 239062 Hom.: 0 AF XY: 0.00000772 AC XY: 1 AN XY: 129484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 24, 2015

The p.Asp1930Gly variant in CDH23 has not been previously reported in individual s with hearing loss, but has been identified in 1/42108 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computa tional prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In summary, the clinical significance of the p.Asp1930Gly varia nt is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	4.4	.;H
PrimateAI	Uncertain	0.60	T
REVEL	Pathogenic	0.94
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.90		Loss of stability (P = 0.0984);Loss of stability (P = 0.0984);
MVP		0.89
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.94
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763582705; hg19: chr10-73545464; COSMIC: COSV56448371;