rs876657760

chr10-71811717-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 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

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]

LOC124902446 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	UniProt
CDH23	NM_022124.6	c.9283A>G	p.Lys3095Glu	missense_variant	65/70	ENST00000224721.12
LOC124902446	XR_007062185.1	n.1042T>C		non_coding_transcript_exon_variant	1/2
CDH23	NM_001171933.1	c.2563A>G	p.Lys855Glu	missense_variant	18/23
CDH23	NM_001171934.1	c.2563A>G	p.Lys855Glu	missense_variant	18/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.9283A>G	p.Lys3095Glu	missense_variant	65/70	5	NM_022124.6	P1

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Jun 19, 2015

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 30, 2021

- -

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
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
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

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: rs876657760; hg19: chr10-73571474;