rs397517322

Positions:

• chr10-71712781-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_022124.6(CDH23):​c.3337G>C​(p.Glu1113Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 9.96

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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Cadherin 11 (size 105) in uniprot entity CAD23_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_022124.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3337G>C	p.Glu1113Gln	missense_variant	28/70	ENST00000224721.12	NP_071407.4
C10orf105	NM_001164375.3	c.*3155C>G		3_prime_UTR_variant	2/2	ENST00000441508.4	NP_001157847.1
CDH23	NM_001171930.2	c.3337G>C	p.Glu1113Gln	missense_variant	28/32		NP_001165401.1
C10orf105	NM_001168390.2	c.*3155C>G		3_prime_UTR_variant	2/2		NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3337G>C	p.Glu1113Gln	missense_variant	28/70	5	NM_022124.6	ENSP00000224721	P1
C10orf105	ENST00000441508.4	c.*3155C>G		3_prime_UTR_variant	2/2	1	NM_001164375.3	ENSP00000403151	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245526 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 133680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000991

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460606 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

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 07, 2013

The Glu1113Gln variant in CDH23 has been reported in one family with Usher syndr ome type III who also carried a second CDH23 variant and two compound heterozygo us variants in another gene (Le Quesne Stabej 2012). It is unclear if any of the variants identified in this family, including Glu1113Gln, are responsible for t heir clinical features. Computational analyses (biochemical amino acid propertie s, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support f or or against an impact to the protein. Additional data is needed to determine t he clinical significance of this variant. -

CDH23-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2024

The CDH23 c.3337G>C variant is predicted to result in the amino acid substitution p.Glu1113Gln. This variant was reported in the homozygous state in an individual with autosomal recessive hearing loss (Table S4, Sloan-Heggen et al. 2015. PubMed ID: 26445815) and in a patient with Usher syndrome along with a second CDH23 variant as well as two potentially causative compound heterozygous variants in another gene (Le Quesne Stabej et al. 2011. PubMed ID: 22135276). This variant is reported in 0.0099% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;D;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.5	.;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
REVEL	Pathogenic	0.81
Sift4G	Pathogenic	0.0	D;D;.;D;.
Polyphen		0.85	.;.;P;.;.
Vest4		0.68
MutPred		0.86		Loss of phosphorylation at S1110 (P = 0.1084);Loss of phosphorylation at S1110 (P = 0.1084);Loss of phosphorylation at S1110 (P = 0.1084);Loss of phosphorylation at S1110 (P = 0.1084);Loss of phosphorylation at S1110 (P = 0.1084);
MVP		0.83
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.36
gMVP		0.89

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: rs397517322; hg19: chr10-73472538;