rs17712523

Variant names:

• chr10-71777857-G-A
• rs17712523
• NM_022124.6:c.5023G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71777857-G-A
• chr10-71777857-G-C
• chr10-71777857-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.5023G>A​(p.Val1675Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,690 control chromosomes in the GnomAD database, including 31,390 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V1675L) has been classified as Uncertain significance. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.15 (2097 hom., cov: 31)
  • Exomes 𝑓: 0.20 (29293 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.115
• 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: 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

ENSG00000306531 (HGNC:):

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020249784).
• BP6: Variant 10-71777857-G-A is Benign according to our data. Variant chr10-71777857-G-A is described in ClinVar as Benign. ClinVar VariationId is 45960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 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.5023G>A	p.Val1675Ile	missense	Exon 39 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.5023G>A	p.Val1675Ile	missense	Exon 39 of 70	ENSP00000224721.9	Q9H251-1
	ENSG00000306531	ENST00000819235.1		n.158-792C>T		intron	N/A
	ENSG00000306531	ENST00000819236.1		n.157-689C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22398 AN: 151948 Hom.: 2097 Cov.: 31

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.179 AC: 44689 AN: 249182 AF XY: 0.183

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.160

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.197 AC: 288436 AN: 1461624 Hom.: 29293 Cov.: 36 AF XY: 0.197 AC XY: 143288 AN XY: 727086

African (AFR) AF: 0.0307 AC: 1027 AN: 33480

American (AMR) AF: 0.142 AC: 6344 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 4756 AN: 26136

East Asian (EAS) AF: 0.145 AC: 5743 AN: 39698

South Asian (SAS) AF: 0.193 AC: 16665 AN: 86252

European-Finnish (FIN) AF: 0.240 AC: 12797 AN: 53380

Middle Eastern (MID) AF: 0.169 AC: 976 AN: 5768

European-Non Finnish (NFE) AF: 0.206 AC: 229340 AN: 1111820

Other (OTH) AF: 0.179 AC: 10788 AN: 60374

GnomAD4 genome AF: 0.147 AC: 22394 AN: 152066 Hom.: 2097 Cov.: 31 AF XY: 0.147 AC XY: 10925 AN XY: 74320

African (AFR) AF: 0.0359 AC: 1490 AN: 41494

American (AMR) AF: 0.127 AC: 1943 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3472

East Asian (EAS) AF: 0.153 AC: 791 AN: 5154

South Asian (SAS) AF: 0.179 AC: 860 AN: 4816

European-Finnish (FIN) AF: 0.242 AC: 2554 AN: 10562

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13640 AN: 67986

Other (OTH) AF: 0.141 AC: 297 AN: 2112

Alfa AF: 0.178 Hom.: 8556

Bravo AF: 0.134

TwinsUK AF: 0.198 AC: 735

ALSPAC AF: 0.204 AC: 785

ESP6500AA AF: 0.0390 AC: 171

ESP6500EA AF: 0.193 AC: 1654

ExAC AF: 0.178 AC: 21619

Asia WGS AF: 0.176 AC: 613 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	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	0.067
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.7
DANN	Benign	0.95
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.12
PrimateAI	Benign	0.24	T
REVEL	Benign	0.014
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.051
ClinPred		0.0028	T
GERP RS		-1.2
Varity_R		0.021
gMVP		0.29
Mutation Taster		=93/7	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: rs17712523; hg19: chr10-73537614; COSMIC: COSV56447054; COSMIC: COSV56447054;