rs76601590

Variant names:

• chr10-71702048-G-A
• rs76601590
• NM_022124.6:c.2424G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71702048-G-A
• chr10-71702048-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):​c.2424G>A​(p.Gly808Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,768 control chromosomes in the GnomAD database, including 1,980 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G808G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (221 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1759 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.16
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-71702048-G-A is Benign according to our data. Variant chr10-71702048-G-A is described in ClinVar as Benign. ClinVar VariationId is 45897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.18 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.2424G>A	p.Gly808Gly	synonymous	Exon 23 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.2424G>A	p.Gly808Gly	synonymous	Exon 23 of 32	NP_001165401.1
	CDH23	NM_001171931.2		c.2424G>A	p.Gly808Gly	synonymous	Exon 23 of 26	NP_001165402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2424G>A	p.Gly808Gly	synonymous	Exon 23 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.2424G>A	p.Gly808Gly	synonymous	Exon 23 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.2424G>A	p.Gly808Gly	synonymous	Exon 23 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3106 AN: 152172 Hom.: 215 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0439 AC: 10921 AN: 248978 AF XY: 0.0366

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.176

Gnomad FIN exome AF: 0.00520

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0146 AC: 21391 AN: 1461478 Hom.: 1759 Cov.: 32 AF XY: 0.0141 AC XY: 10265 AN XY: 727022

African (AFR) AF: 0.00215 AC: 72 AN: 33480

American (AMR) AF: 0.176 AC: 7852 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 380 AN: 26134

East Asian (EAS) AF: 0.201 AC: 7960 AN: 39700

South Asian (SAS) AF: 0.0242 AC: 2084 AN: 86258

European-Finnish (FIN) AF: 0.00532 AC: 283 AN: 53204

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5766

European-Non Finnish (NFE) AF: 0.00117 AC: 1303 AN: 1111854

Other (OTH) AF: 0.0220 AC: 1328 AN: 60368

GnomAD4 genome AF: 0.0206 AC: 3130 AN: 152290 Hom.: 221 Cov.: 32 AF XY: 0.0228 AC XY: 1701 AN XY: 74454

African (AFR) AF: 0.00286 AC: 119 AN: 41568

American (AMR) AF: 0.106 AC: 1626 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.190 AC: 980 AN: 5168

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4826

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10628

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68010

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0119 Hom.: 88

Bravo AF: 0.0301

Asia WGS AF: 0.0870 AC: 301 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.9
DANN	Benign	0.46
PhyloP100		-1.2
Mutation Taster		=95/5	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: rs76601590; hg19: chr10-73461805; COSMIC: COSV54936484;