rs11592462

Variant names:

• chr10-71790360-C-G
• rs11592462
• NM_022124.6:c.5996C>G

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.5996C>G​(p.Thr1999Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,008 control chromosomes in the GnomAD database, including 179,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T1999T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13508 hom., cov: 33)
  • Exomes 𝑓: 0.47 (165980 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.70
• Publications: 39 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: PanelApp Australia, 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: PanelApp Australia, 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=5.040169E-4).
• BP6: Variant 10-71790360-C-G is Benign according to our data. Variant chr10-71790360-C-G is described in ClinVar as Benign. ClinVar VariationId is 45997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 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.5996C>G	p.Thr1999Ser	missense	Exon 46 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.5996C>G	p.Thr1999Ser	missense	Exon 46 of 70	ENSP00000224721.9	Q9H251-1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62191 AN: 151952 Hom.: 13501 Cov.: 33

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.430

GnomAD2 exomes AF: 0.423 AC: 104457 AN: 246988 AF XY: 0.439

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.470 AC: 687244 AN: 1460938 Hom.: 165980 Cov.: 48 AF XY: 0.473 AC XY: 344012 AN XY: 726756

African (AFR) AF: 0.276 AC: 9254 AN: 33474

American (AMR) AF: 0.302 AC: 13474 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 13686 AN: 26122

East Asian (EAS) AF: 0.141 AC: 5602 AN: 39690

South Asian (SAS) AF: 0.518 AC: 44665 AN: 86216

European-Finnish (FIN) AF: 0.428 AC: 22730 AN: 53112

Middle Eastern (MID) AF: 0.498 AC: 2872 AN: 5764

European-Non Finnish (NFE) AF: 0.493 AC: 547463 AN: 1111530

Other (OTH) AF: 0.456 AC: 27498 AN: 60354

GnomAD4 genome AF: 0.409 AC: 62204 AN: 152070 Hom.: 13508 Cov.: 33 AF XY: 0.406 AC XY: 30193 AN XY: 74332

African (AFR) AF: 0.288 AC: 11953 AN: 41492

American (AMR) AF: 0.367 AC: 5604 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1835 AN: 3468

East Asian (EAS) AF: 0.165 AC: 854 AN: 5172

South Asian (SAS) AF: 0.512 AC: 2464 AN: 4816

European-Finnish (FIN) AF: 0.427 AC: 4506 AN: 10562

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33562 AN: 67960

Other (OTH) AF: 0.434 AC: 915 AN: 2110

Alfa AF: 0.474 Hom.: 13287

Bravo AF: 0.392

TwinsUK AF: 0.485 AC: 1800

ALSPAC AF: 0.495 AC: 1907

ESP6500AA AF: 0.270 AC: 1130

ESP6500EA AF: 0.486 AC: 4091

ExAC AF: 0.426 AC: 51511

Asia WGS AF: 0.331 AC: 1154 AN: 3478

EpiCase AF: 0.500

EpiControl AF: 0.499

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (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	0.088
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.00050	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.39	N
PhyloP100		1.7
PrimateAI	Benign	0.41	T
REVEL	Benign	0.086
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.47		Gain of phosphorylation at Y1995 (P = 0.2156)
ClinPred		0.014	T
GERP RS		4.1
Varity_R		0.099
gMVP		0.26
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11592462; hg19: chr10-73550117; COSMIC: COSV56463992; COSMIC: COSV56463992;