rs56216952

Variant names:

• chr10-71706913-C-T
• rs56216952
• NM_022124.6:c.2970C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.2970C>T​(p.Asp990Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,602,638 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (23 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.724
• Publications: 4 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

ENSG00000300551 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 10-71706913-C-T is Benign according to our data. Variant chr10-71706913-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44110.
• BP7: Synonymous conserved (PhyloP=-0.724 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0028 (426/152360) while in subpopulation NFE AF = 0.00454 (309/68030). AF 95% confidence interval is 0.00412. There are 1 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.2970C>T	p.Asp990Asp	synonymous	Exon 26 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.2970C>T	p.Asp990Asp	synonymous	Exon 26 of 32	NP_001165401.1
	CDH23	NM_001171931.2		c.2970C>T	p.Asp990Asp	synonymous	Exon 26 of 26	NP_001165402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2970C>T	p.Asp990Asp	synonymous	Exon 26 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.2970C>T	p.Asp990Asp	synonymous	Exon 26 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.2970C>T	p.Asp990Asp	synonymous	Exon 26 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152242 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00336 AC: 771 AN: 229170 AF XY: 0.00318

Gnomad AFR exome AF: 0.000230

Gnomad AMR exome AF: 0.000704

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00621

Gnomad OTH exome AF: 0.00227

GnomAD4 exome AF: 0.00459 AC: 6659 AN: 1450278 Hom.: 23 Cov.: 31 AF XY: 0.00449 AC XY: 3237 AN XY: 720204

African (AFR) AF: 0.000482 AC: 16 AN: 33216

American (AMR) AF: 0.000671 AC: 29 AN: 43244

Ashkenazi Jewish (ASJ) AF: 0.000194 AC: 5 AN: 25814

East Asian (EAS) AF: 0.00 AC: 0 AN: 39098

South Asian (SAS) AF: 0.000298 AC: 25 AN: 83912

European-Finnish (FIN) AF: 0.00467 AC: 244 AN: 52238

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.00554 AC: 6133 AN: 1107036

Other (OTH) AF: 0.00337 AC: 202 AN: 59976

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152360 Hom.: 1 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74502

African (AFR) AF: 0.000553 AC: 23 AN: 41580

American (AMR) AF: 0.000784 AC: 12 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00454 AC: 309 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00404 Hom.: 1

Bravo AF: 0.00279

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	Usher syndrome type 1D (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	6.4
DANN	Benign	0.90
PhyloP100		-0.72
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

Other links and lift over

dbSNP: rs56216952; hg19: chr10-73466670;