rs201733315

Variant names:

• chr10-71805955-G-A
• rs201733315
• NM_022124.6:c.8022G>A
• CDH23 p.Gln2674Gln

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.8022G>A​(p.Gln2674Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0071 in 1,612,308 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (36 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.67
• Publications: 2 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

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-71805955-G-A is Benign according to our data. Variant chr10-71805955-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46043.
• BP7: Synonymous conserved (PhyloP=1.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0052 (791/152048) while in subpopulation NFE AF = 0.00828 (563/67972). AF 95% confidence interval is 0.00772. There are 1 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 36 AR,Unknown gene

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.8022G>A	p.Gln2674Gln	synonymous	Exon 56 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.1302G>A	p.Gln434Gln	synonymous	Exon 9 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.1302G>A	p.Gln434Gln	synonymous	Exon 9 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.8022G>A	p.Gln2674Gln	synonymous	Exon 56 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.1558G>A		non_coding_transcript_exon	Exon 8 of 21
	CDH23	ENST00000642965.1		n.*1865G>A		non_coding_transcript_exon	Exon 11 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 793 AN: 151928 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00590

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00418

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00831

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00530 AC: 1311 AN: 247160 AF XY: 0.00531

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.00380

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00229

Gnomad NFE exome AF: 0.00854

Gnomad OTH exome AF: 0.00516

GnomAD4 exome AF: 0.00730 AC: 10661 AN: 1460260 Hom.: 36 Cov.: 32 AF XY: 0.00711 AC XY: 5168 AN XY: 726378

African (AFR) AF: 0.00120 AC: 40 AN: 33466

American (AMR) AF: 0.00320 AC: 143 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00391 AC: 102 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00369 AC: 318 AN: 86094

European-Finnish (FIN) AF: 0.00231 AC: 122 AN: 52910

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.00864 AC: 9599 AN: 1111356

Other (OTH) AF: 0.00529 AC: 319 AN: 60306

GnomAD4 genome AF: 0.00520 AC: 791 AN: 152048 Hom.: 1 Cov.: 32 AF XY: 0.00510 AC XY: 379 AN XY: 74332

African (AFR) AF: 0.00147 AC: 61 AN: 41508

American (AMR) AF: 0.00589 AC: 90 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4818

European-Finnish (FIN) AF: 0.00418 AC: 44 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00828 AC: 563 AN: 67972

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00595 Hom.: 1

Bravo AF: 0.00490

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00763

EpiControl AF: 0.00825

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1D (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	CDH23-related disorder (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201733315;

hg19: chr10-73565712;