10-71813280-C-T

Variant names:

• chr10-71813280-C-T
• rs111033457
• NM_022124.6:c.9670C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_022124.6(CDH23):​c.9670C>T​(p.Arg3224Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,551,642 control chromosomes in the GnomAD database, including 5 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. R3224Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:3
• Conservation: PhyloP100: 4.70
• Publications: 6 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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12823543).
• BP6: Variant 10-71813280-C-T is Benign according to our data. Variant chr10-71813280-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46078.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00102 (155/152294) while in subpopulation NFE AF = 0.00185 (126/68018). AF 95% confidence interval is 0.00159. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.9670C>T	p.Arg3224Trp	missense	Exon 69 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.2950C>T	p.Arg984Trp	missense	Exon 22 of 23	NP_001165404.1
	CDH23	NM_001171935.1		c.361C>T	p.Arg121Trp	missense	Exon 4 of 5	NP_001165406.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9670C>T	p.Arg3224Trp	missense	Exon 69 of 70	ENSP00000224721.9
	CDH23	ENST00000475158.1	TSL:1	n.3169+390C>T		intron	N/A
	CDH23	ENST00000642965.1		n.*3513C>T		non_coding_transcript_exon	Exon 24 of 25	ENSP00000495222.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000841 AC: 131 AN: 155776 AF XY: 0.000849

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.000822

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.00107 AC: 1504 AN: 1399348 Hom.: 5 Cov.: 32 AF XY: 0.00114 AC XY: 788 AN XY: 690182

African (AFR) AF: 0.000158 AC: 5 AN: 31598

American (AMR) AF: 0.000196 AC: 7 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 19 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000883 AC: 7 AN: 79236

European-Finnish (FIN) AF: 0.00223 AC: 110 AN: 49240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00122 AC: 1316 AN: 1078962

Other (OTH) AF: 0.000690 AC: 40 AN: 58000

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74468

African (AFR) AF: 0.000217 AC: 9 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00185 AC: 126 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00139 Hom.: 1

Bravo AF: 0.000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000456 AC: 3

ExAC AF: 0.000384 AC: 15

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
-	5	2	not provided (7)
-	1	1	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	1	-	CDH23-related disorder (1)
-	1	-	Retinal dystrophy (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	Uncertain	0.44
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.086	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.92
MPC		0.26
ClinPred		0.066	T
GERP RS		5.5
Varity_R		0.47
gMVP		0.67
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs111033457; hg19: chr10-73573037;