rs114745089

Variant names:

• chr10-71779376-T-C
• rs114745089
• NM_022124.6:c.5297T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.5297T>C​(p.Phe1766Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,613,856 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1766L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 7.80
• Publications: 2 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

ENSG00000306531 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008866727).
• BP6: Variant 10-71779376-T-C is Benign according to our data. Variant chr10-71779376-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45973.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00464 (707/152232) while in subpopulation AFR AF = 0.0164 (682/41542). AF 95% confidence interval is 0.0154. There are 6 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.5297T>C	p.Phe1766Ser	missense	Exon 41 of 70	NP_071407.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.5297T>C	p.Phe1766Ser	missense	Exon 41 of 70	ENSP00000224721.9
	ENSG00000306531	ENST00000819235.1		n.158-2311A>G		intron	N/A
	ENSG00000306531	ENST00000819236.1		n.157-2208A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00464 AC: 706 AN: 152114 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00106 AC: 265 AN: 248944 AF XY: 0.000740

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000454 AC: 664 AN: 1461624 Hom.: 4 Cov.: 31 AF XY: 0.000363 AC XY: 264 AN XY: 727096

African (AFR) AF: 0.0171 AC: 574 AN: 33478

American (AMR) AF: 0.000716 AC: 32 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111828

Other (OTH) AF: 0.000812 AC: 49 AN: 60368

GnomAD4 genome AF: 0.00464 AC: 707 AN: 152232 Hom.: 6 Cov.: 33 AF XY: 0.00465 AC XY: 346 AN XY: 74420

African (AFR) AF: 0.0164 AC: 682 AN: 41542

American (AMR) AF: 0.00124 AC: 19 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00104 Hom.: 3

Bravo AF: 0.00507

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0135 AC: 54

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00127 AC: 154

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	1	-	CDH23-related disorder (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.8
PrimateAI	Uncertain	0.60	T
REVEL	Benign	0.22
Sift4G	Uncertain	0.0040	D
Polyphen		0.93	P
Vest4		0.93
MVP		0.87
ClinPred		0.018	T
GERP RS		5.0
Varity_R		0.60
gMVP		0.75
Mutation Taster		=91/9	polymorphism

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: rs114745089; hg19: chr10-73539133;