rs4747194

Variant names:

• chr10-71799129-G-A
• rs4747194
• NM_022124.6:c.7073G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71799129-G-A
• chr10-71799129-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.7073G>A​(p.Arg2358Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,613,004 control chromosomes in the GnomAD database, including 71,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict 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. R2358W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (6585 hom., cov: 33)
  • Exomes 𝑓: 0.29 (65112 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.850
• Publications: 38 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 -16 ACMG points.

• BP6: Variant 10-71799129-G-A is Benign according to our data. Variant chr10-71799129-G-A is described in ClinVar as Benign. ClinVar VariationId is 46026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 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.7073G>A	p.Arg2358Gln	missense	Exon 51 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.353G>A	p.Arg118Gln	missense	Exon 4 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.353G>A	p.Arg118Gln	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.7073G>A	p.Arg2358Gln	missense	Exon 51 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.609G>A		non_coding_transcript_exon	Exon 3 of 21
	CDH23	ENST00000642965.1		n.*916G>A		non_coding_transcript_exon	Exon 6 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43751 AN: 151980 Hom.: 6581 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.315 AC: 78310 AN: 248704 AF XY: 0.304

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.530

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.292 AC: 426043 AN: 1460906 Hom.: 65112 Cov.: 36 AF XY: 0.288 AC XY: 209353 AN XY: 726744

African (AFR) AF: 0.268 AC: 8984 AN: 33464

American (AMR) AF: 0.420 AC: 18759 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5834 AN: 26114

East Asian (EAS) AF: 0.575 AC: 22836 AN: 39684

South Asian (SAS) AF: 0.256 AC: 22111 AN: 86228

European-Finnish (FIN) AF: 0.345 AC: 18408 AN: 53376

Middle Eastern (MID) AF: 0.174 AC: 1005 AN: 5768

European-Non Finnish (NFE) AF: 0.279 AC: 310514 AN: 1111218

Other (OTH) AF: 0.291 AC: 17592 AN: 60354

GnomAD4 genome AF: 0.288 AC: 43770 AN: 152098 Hom.: 6585 Cov.: 33 AF XY: 0.292 AC XY: 21672 AN XY: 74332

African (AFR) AF: 0.267 AC: 11089 AN: 41488

American (AMR) AF: 0.332 AC: 5084 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3470

East Asian (EAS) AF: 0.532 AC: 2743 AN: 5152

South Asian (SAS) AF: 0.270 AC: 1304 AN: 4824

European-Finnish (FIN) AF: 0.346 AC: 3663 AN: 10576

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18165 AN: 67980

Other (OTH) AF: 0.266 AC: 562 AN: 2112

Alfa AF: 0.275 Hom.: 23525

Bravo AF: 0.292

TwinsUK AF: 0.291 AC: 1078

ALSPAC AF: 0.281 AC: 1084

ESP6500AA AF: 0.263 AC: 1060

ESP6500EA AF: 0.261 AC: 2191

ExAC AF: 0.307 AC: 37081

Asia WGS AF: 0.364 AC: 1267 AN: 3478

EpiCase AF: 0.256

EpiControl AF: 0.258

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.00033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.85
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.071
Sift	Benign	0.34	T
Sift4G	Benign	0.16	T
Polyphen		0.027	B
Vest4		0.044
MPC		0.17
ClinPred		0.026	T
GERP RS		2.7
Varity_R		0.19
gMVP		0.34
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4747194; hg19: chr10-73558886; COSMIC: COSV56452480;