rs10999947

Variant names:

• chr10-71675149-G-A
• rs10999947
• NM_022124.6:c.1487G>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.1487G>A​(p.Ser496Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,612,966 control chromosomes in the GnomAD database, including 60,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. S496I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (5568 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54747 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.420
• Publications: 37 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=0.006324768).
• BP6: Variant 10-71675149-G-A is Benign according to our data. Variant chr10-71675149-G-A is described in ClinVar as Benign. ClinVar VariationId is 45875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.289 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.1487G>A	p.Ser496Asn	missense	Exon 15 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.1487G>A	p.Ser496Asn	missense	Exon 15 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.1487G>A	p.Ser496Asn	missense	Exon 15 of 26	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.1487G>A	p.Ser496Asn	missense	Exon 15 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.1487G>A	p.Ser496Asn	missense	Exon 15 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.1487G>A	p.Ser496Asn	missense	Exon 15 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41019 AN: 152038 Hom.: 5559 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.274 AC: 68122 AN: 249022 AF XY: 0.272

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.306

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.297

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.272 AC: 396639 AN: 1460810 Hom.: 54747 Cov.: 34 AF XY: 0.271 AC XY: 196966 AN XY: 726734

African (AFR) AF: 0.258 AC: 8649 AN: 33472

American (AMR) AF: 0.304 AC: 13596 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4855 AN: 26130

East Asian (EAS) AF: 0.244 AC: 9701 AN: 39690

South Asian (SAS) AF: 0.272 AC: 23458 AN: 86236

European-Finnish (FIN) AF: 0.306 AC: 16340 AN: 53366

Middle Eastern (MID) AF: 0.258 AC: 1488 AN: 5766

European-Non Finnish (NFE) AF: 0.272 AC: 302019 AN: 1111102

Other (OTH) AF: 0.274 AC: 16533 AN: 60348

GnomAD4 genome AF: 0.270 AC: 41072 AN: 152156 Hom.: 5568 Cov.: 32 AF XY: 0.272 AC XY: 20224 AN XY: 74396

African (AFR) AF: 0.257 AC: 10656 AN: 41486

American (AMR) AF: 0.296 AC: 4524 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 648 AN: 3470

East Asian (EAS) AF: 0.269 AC: 1395 AN: 5186

South Asian (SAS) AF: 0.260 AC: 1254 AN: 4828

European-Finnish (FIN) AF: 0.310 AC: 3285 AN: 10592

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18439 AN: 67990

Other (OTH) AF: 0.276 AC: 583 AN: 2114

Alfa AF: 0.267 Hom.: 25058

Bravo AF: 0.268

TwinsUK AF: 0.256 AC: 950

ALSPAC AF: 0.282 AC: 1088

ESP6500AA AF: 0.230 AC: 963

ESP6500EA AF: 0.260 AC: 2193

ExAC AF: 0.272 AC: 32861

Asia WGS AF: 0.261 AC: 907 AN: 3478

EpiCase AF: 0.258

EpiControl AF: 0.256

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (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	0.064
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.70
DANN	Benign	0.44
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.064	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.42
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.070
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.056
ClinPred		0.0030	T
GERP RS		-0.61
Varity_R		0.047
gMVP		0.37
Mutation Taster		=97/3	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: rs10999947; hg19: chr10-73434906; COSMIC: COSV99819113;