NM_022124.6:c.5411G>A

Variant names:

• chr10-71784329-G-A
• rs3802711
• NM_022124.6:c.5411G>A

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.5411G>A​(p.Arg1804Gln) variant causes a missense change. The variant allele was found at a frequency of 0.169 in 1,613,564 control chromosomes in the GnomAD database, including 24,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1804W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1707 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22582 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 6.57
• Publications: 40 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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017862618).
• BP6: Variant 10-71784329-G-A is Benign according to our data. Variant chr10-71784329-G-A is described in ClinVar as Benign. ClinVar VariationId is 45978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 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.5411G>A	p.Arg1804Gln	missense	Exon 42 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.5411G>A	p.Arg1804Gln	missense	Exon 42 of 70	ENSP00000224721.9	Q9H251-1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21573 AN: 152092 Hom.: 1708 Cov.: 33

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.155 AC: 38608 AN: 249008 AF XY: 0.154

Gnomad AFR exome AF: 0.0714

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.237

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.172 AC: 251202 AN: 1461354 Hom.: 22582 Cov.: 33 AF XY: 0.170 AC XY: 123285 AN XY: 726992

African (AFR) AF: 0.0721 AC: 2414 AN: 33478

American (AMR) AF: 0.109 AC: 4873 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3299 AN: 26120

East Asian (EAS) AF: 0.272 AC: 10788 AN: 39692

South Asian (SAS) AF: 0.106 AC: 9179 AN: 86226

European-Finnish (FIN) AF: 0.208 AC: 11124 AN: 53388

Middle Eastern (MID) AF: 0.0992 AC: 572 AN: 5764

European-Non Finnish (NFE) AF: 0.179 AC: 199165 AN: 1111650

Other (OTH) AF: 0.162 AC: 9788 AN: 60356

GnomAD4 genome AF: 0.142 AC: 21576 AN: 152210 Hom.: 1707 Cov.: 33 AF XY: 0.143 AC XY: 10655 AN XY: 74416

African (AFR) AF: 0.0745 AC: 3095 AN: 41540

American (AMR) AF: 0.130 AC: 1987 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3472

East Asian (EAS) AF: 0.247 AC: 1277 AN: 5166

South Asian (SAS) AF: 0.108 AC: 523 AN: 4826

European-Finnish (FIN) AF: 0.213 AC: 2257 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11571 AN: 67988

Other (OTH) AF: 0.136 AC: 287 AN: 2114

Alfa AF: 0.161 Hom.: 4971

Bravo AF: 0.134

TwinsUK AF: 0.182 AC: 675

ALSPAC AF: 0.174 AC: 670

ESP6500AA AF: 0.0779 AC: 310

ESP6500EA AF: 0.164 AC: 1367

ExAC AF: 0.154 AC: 18664

Asia WGS AF: 0.129 AC: 448 AN: 3478

EpiCase AF: 0.164

EpiControl AF: 0.167

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	0.096
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.014	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.59	N
PhyloP100		6.6
PrimateAI	Uncertain	0.53	T
REVEL	Benign	0.24
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.50
ClinPred		0.0074	T
GERP RS		5.4
Varity_R		0.57
gMVP		0.56
Mutation Taster		=76/24	polymorphism (auto)

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: rs3802711; hg19: chr10-73544086; COSMIC: COSV56447084;