rs2290021

Variant names:

• chr10-71815086-G-A
• rs2290021
• NM_022124.6:c.9873G>A

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.9873G>A​(p.Thr3291Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0967 in 1,610,376 control chromosomes in the GnomAD database, including 9,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (896 hom., cov: 34)
  • Exomes 𝑓: 0.097 (9070 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -3.53
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-71815086-G-A is Benign according to our data. Variant chr10-71815086-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.273 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.9873G>A	p.Thr3291Thr	synonymous	Exon 70 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.3153G>A	p.Thr1051Thr	synonymous	Exon 23 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.3048G>A	p.Thr1016Thr	synonymous	Exon 22 of 22	NP_001165405.1	Q9H251-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9873G>A	p.Thr3291Thr	synonymous	Exon 70 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.3304G>A		non_coding_transcript_exon	Exon 21 of 21
	CDH23	ENST00000642965.1		n.*3716G>A		non_coding_transcript_exon	Exon 25 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.0917 AC: 13958 AN: 152210 Hom.: 894 Cov.: 34

Gnomad AFR AF: 0.0490

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.0570

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0800

Gnomad OTH AF: 0.0812

GnomAD2 exomes AF: 0.132 AC: 31820 AN: 240552 AF XY: 0.122

Gnomad AFR exome AF: 0.0478

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.295

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.0780

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.0973 AC: 141839 AN: 1458048 Hom.: 9070 Cov.: 32 AF XY: 0.0957 AC XY: 69422 AN XY: 725224

African (AFR) AF: 0.0448 AC: 1498 AN: 33440

American (AMR) AF: 0.293 AC: 12942 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 1499 AN: 26036

East Asian (EAS) AF: 0.301 AC: 11900 AN: 39584

South Asian (SAS) AF: 0.104 AC: 8887 AN: 85864

European-Finnish (FIN) AF: 0.129 AC: 6713 AN: 52172

Middle Eastern (MID) AF: 0.0326 AC: 188 AN: 5764

European-Non Finnish (NFE) AF: 0.0829 AC: 92082 AN: 1110810

Other (OTH) AF: 0.102 AC: 6130 AN: 60234

GnomAD4 genome AF: 0.0917 AC: 13962 AN: 152328 Hom.: 896 Cov.: 34 AF XY: 0.0960 AC XY: 7151 AN XY: 74484

African (AFR) AF: 0.0489 AC: 2034 AN: 41580

American (AMR) AF: 0.171 AC: 2618 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0570 AC: 198 AN: 3472

East Asian (EAS) AF: 0.285 AC: 1476 AN: 5182

South Asian (SAS) AF: 0.117 AC: 567 AN: 4828

European-Finnish (FIN) AF: 0.127 AC: 1345 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0800 AC: 5439 AN: 68010

Other (OTH) AF: 0.0808 AC: 171 AN: 2116

Alfa AF: 0.0861 Hom.: 454

Bravo AF: 0.0988

Asia WGS AF: 0.201 AC: 696 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Atypical Gaucher Disease (1)
-	-	1	Combined PSAP deficiency (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	Hearing loss, autosomal recessive (1)
-	-	1	Metachromatic leukodystrophy (1)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.22
DANN	Benign	0.90
PhyloP100		-3.5
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2290021; hg19: chr10-73574843; COSMIC: COSV56446643; COSMIC: COSV56446643;