rs10466026

Variant names:

• chr10-71791212-G-A
• rs10466026
• NM_022124.6:c.6130G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71791212-G-A
• chr10-71791212-G-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.6130G>A​(p.Glu2044Lys) variant causes a missense change. The variant allele was found at a frequency of 0.289 in 1,612,844 control chromosomes in the GnomAD database, including 70,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6533 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63969 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.85
• Publications: 41 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, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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=0.0011279583).
• BP6: Variant 10-71791212-G-A is Benign according to our data. Variant chr10-71791212-G-A is described in ClinVar as Benign. ClinVar VariationId is 46002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 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.6130G>A	p.Glu2044Lys	missense	Exon 47 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.6130G>A	p.Glu2044Lys	missense	Exon 47 of 70	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43472 AN: 152008 Hom.: 6526 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.309 AC: 76554 AN: 247484 AF XY: 0.297

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.529

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.289 AC: 421828 AN: 1460718 Hom.: 63969 Cov.: 37 AF XY: 0.284 AC XY: 206636 AN XY: 726558

African (AFR) AF: 0.268 AC: 8952 AN: 33458

American (AMR) AF: 0.418 AC: 18615 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5535 AN: 26122

East Asian (EAS) AF: 0.575 AC: 22811 AN: 39660

South Asian (SAS) AF: 0.227 AC: 19563 AN: 86106

European-Finnish (FIN) AF: 0.347 AC: 18490 AN: 53290

Middle Eastern (MID) AF: 0.161 AC: 930 AN: 5768

European-Non Finnish (NFE) AF: 0.279 AC: 309557 AN: 1111446

Other (OTH) AF: 0.288 AC: 17375 AN: 60336

GnomAD4 genome AF: 0.286 AC: 43495 AN: 152126 Hom.: 6533 Cov.: 32 AF XY: 0.290 AC XY: 21542 AN XY: 74366

African (AFR) AF: 0.265 AC: 11010 AN: 41508

American (AMR) AF: 0.332 AC: 5072 AN: 15278

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

East Asian (EAS) AF: 0.534 AC: 2756 AN: 5164

South Asian (SAS) AF: 0.243 AC: 1174 AN: 4826

European-Finnish (FIN) AF: 0.348 AC: 3691 AN: 10594

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

European-Non Finnish (NFE) AF: 0.266 AC: 18107 AN: 67972

Other (OTH) AF: 0.266 AC: 560 AN: 2106

Alfa AF: 0.272 Hom.: 14382

Bravo AF: 0.290

TwinsUK AF: 0.290 AC: 1076

ALSPAC AF: 0.280 AC: 1079

ESP6500AA AF: 0.270 AC: 1189

ESP6500EA AF: 0.263 AC: 2258

ExAC AF: 0.300 AC: 36393

Asia WGS AF: 0.348 AC: 1212 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	0.070
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.072
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.72	N
PhyloP100		3.8
PrimateAI	Uncertain	0.51	T
REVEL	Benign	0.18
Sift4G	Uncertain	0.041	D
Polyphen		0.64	P
Vest4		0.48
ClinPred		0.022	T
GERP RS		5.9
Varity_R		0.13
gMVP		0.64
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10466026; hg19: chr10-73550969; COSMIC: COSV56449572; COSMIC: COSV56449572;