rs45583140

Variant names:

• chr10-71812008-T-C
• rs45583140
• NM_022124.6:c.9373T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.9373T>C​(p.Phe3125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0501 in 1,612,768 control chromosomes in the GnomAD database, including 3,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F3125S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.045 (328 hom., cov: 33)
  • Exomes 𝑓: 0.051 (3442 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 5.75
• Publications: 19 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
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902446 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020181537).
• BP6: Variant 10-71812008-T-C is Benign according to our data. Variant chr10-71812008-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

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.9373T>C	p.Phe3125Leu	missense	Exon 66 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.2653T>C	p.Phe885Leu	missense	Exon 19 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.2653T>C	p.Phe885Leu	missense	Exon 19 of 22	NP_001165405.1	Q9H251-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9373T>C	p.Phe3125Leu	missense	Exon 66 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.2909T>C		non_coding_transcript_exon	Exon 18 of 21
	CDH23	ENST00000642965.1		n.*3216T>C		non_coding_transcript_exon	Exon 21 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6853 AN: 151384 Hom.: 328 Cov.: 33

Gnomad AFR AF: 0.00978

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0726

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.0917

Gnomad FIN AF: 0.0943

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0421

GnomAD2 exomes AF: 0.0739 AC: 18420 AN: 249186 AF XY: 0.0702

Gnomad AFR exome AF: 0.00949

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.251

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.0358

Gnomad OTH exome AF: 0.0574

GnomAD4 exome AF: 0.0506 AC: 73952 AN: 1461266 Hom.: 3442 Cov.: 48 AF XY: 0.0506 AC XY: 36816 AN XY: 726924

African (AFR) AF: 0.00720 AC: 241 AN: 33474

American (AMR) AF: 0.125 AC: 5609 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1224 AN: 26114

East Asian (EAS) AF: 0.277 AC: 10978 AN: 39686

South Asian (SAS) AF: 0.0769 AC: 6636 AN: 86256

European-Finnish (FIN) AF: 0.0898 AC: 4794 AN: 53370

Middle Eastern (MID) AF: 0.0192 AC: 111 AN: 5768

European-Non Finnish (NFE) AF: 0.0367 AC: 40817 AN: 1111550

Other (OTH) AF: 0.0587 AC: 3542 AN: 60346

GnomAD4 genome AF: 0.0452 AC: 6852 AN: 151502 Hom.: 328 Cov.: 33 AF XY: 0.0501 AC XY: 3710 AN XY: 74014

African (AFR) AF: 0.00975 AC: 402 AN: 41224

American (AMR) AF: 0.0725 AC: 1104 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3468

East Asian (EAS) AF: 0.248 AC: 1270 AN: 5116

South Asian (SAS) AF: 0.0920 AC: 443 AN: 4814

European-Finnish (FIN) AF: 0.0943 AC: 985 AN: 10440

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.0351 AC: 2386 AN: 67894

Other (OTH) AF: 0.0427 AC: 90 AN: 2110

Alfa AF: 0.0418 Hom.: 978

Bravo AF: 0.0444

TwinsUK AF: 0.0383 AC: 142

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.0106 AC: 42

ESP6500EA AF: 0.0326 AC: 271

ExAC AF: 0.0696 AC: 8411

Asia WGS AF: 0.167 AC: 580 AN: 3478

EpiCase AF: 0.0346

EpiControl AF: 0.0324

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	Retinitis pigmentosa-deafness syndrome (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Atypical Gaucher Disease (1)
-	-	1	Combined PSAP deficiency (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	Hearing loss, autosomal recessive (1)
-	-	1	Metachromatic leukodystrophy (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.11
Sift	Benign	0.094	T
Sift4G	Uncertain	0.011	D
Polyphen		0.90	P
Vest4		0.66
MutPred		0.60		Loss of stability (P = 0.1003)
MPC		0.17
ClinPred		0.015	T
GERP RS		5.8
Varity_R		0.45
gMVP		0.68
Mutation Taster		=85/15	polymorphism (auto)

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: rs45583140; hg19: chr10-73571765; COSMIC: COSV56453736; COSMIC: COSV56453736;