rs4747195

Variant names:

• chr10-71799195-C-T
• rs4747195
• NM_022124.6:c.7139C>T

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.7139C>T​(p.Pro2380Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,613,748 control chromosomes in the GnomAD database, including 70,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2380P) has been classified as Likely benign. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.28 (6316 hom., cov: 33)
  • Exomes 𝑓: 0.29 (63787 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.88
• Publications: 44 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

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003720373).
• BP6: Variant 10-71799195-C-T is Benign according to our data. Variant chr10-71799195-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.515 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.7139C>T	p.Pro2380Leu	missense	Exon 51 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.419C>T	p.Pro140Leu	missense	Exon 4 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.419C>T	p.Pro140Leu	missense	Exon 4 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.7139C>T	p.Pro2380Leu	missense	Exon 51 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.675C>T		non_coding_transcript_exon	Exon 3 of 21
	CDH23	ENST00000642965.1		n.*982C>T		non_coding_transcript_exon	Exon 6 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42635 AN: 151990 Hom.: 6312 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.260

GnomAD2 exomes AF: 0.308 AC: 76764 AN: 249150 AF XY: 0.296

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.530

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.281

GnomAD4 exome AF: 0.288 AC: 421080 AN: 1461638 Hom.: 63787 Cov.: 37 AF XY: 0.284 AC XY: 206338 AN XY: 727114

African (AFR) AF: 0.248 AC: 8290 AN: 33478

American (AMR) AF: 0.417 AC: 18648 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5545 AN: 26136

East Asian (EAS) AF: 0.575 AC: 22840 AN: 39698

South Asian (SAS) AF: 0.227 AC: 19603 AN: 86252

European-Finnish (FIN) AF: 0.345 AC: 18411 AN: 53402

Middle Eastern (MID) AF: 0.159 AC: 916 AN: 5768

European-Non Finnish (NFE) AF: 0.278 AC: 309564 AN: 1111818

Other (OTH) AF: 0.286 AC: 17263 AN: 60372

GnomAD4 genome AF: 0.280 AC: 42650 AN: 152110 Hom.: 6316 Cov.: 33 AF XY: 0.284 AC XY: 21138 AN XY: 74338

African (AFR) AF: 0.248 AC: 10295 AN: 41494

American (AMR) AF: 0.330 AC: 5040 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 739 AN: 3472

East Asian (EAS) AF: 0.532 AC: 2740 AN: 5152

South Asian (SAS) AF: 0.244 AC: 1173 AN: 4814

European-Finnish (FIN) AF: 0.345 AC: 3656 AN: 10584

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18078 AN: 67982

Other (OTH) AF: 0.258 AC: 545 AN: 2116

Alfa AF: 0.272 Hom.: 15195

Bravo AF: 0.284

TwinsUK AF: 0.290 AC: 1076

ALSPAC AF: 0.280 AC: 1080

ESP6500AA AF: 0.240 AC: 966

ESP6500EA AF: 0.261 AC: 2173

ExAC AF: 0.299 AC: 36197

Asia WGS AF: 0.348 AC: 1210 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.256

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-9.5	D
REVEL	Benign	0.26
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MPC		0.31
ClinPred		0.068	T
GERP RS		5.5
Varity_R		0.89
gMVP		0.72
Mutation Taster		=30/70	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4747195; hg19: chr10-73558952; COSMIC: COSV56452490;