10-71803270-C-T

Variant names:

• chr10-71803270-C-T
• rs111033483
• NM_022124.6:c.7722C>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.7722C>T​(p.Tyr2574Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,593,284 control chromosomes in the GnomAD database, including 18 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 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (15 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -3.36
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 10-71803270-C-T is Benign according to our data. Variant chr10-71803270-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46037.
• BP7: Synonymous conserved (PhyloP=-3.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00281 (428/152322) while in subpopulation NFE AF = 0.00487 (331/68022). AF 95% confidence interval is 0.00443. There are 3 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.7722C>T	p.Tyr2574Tyr	synonymous	Exon 55 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.1002C>T	p.Tyr334Tyr	synonymous	Exon 8 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.1002C>T	p.Tyr334Tyr	synonymous	Exon 8 of 22	NP_001165405.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.7722C>T	p.Tyr2574Tyr	synonymous	Exon 55 of 70	ENSP00000224721.9
	CDH23	ENST00000475158.1	TSL:1	n.1258C>T		non_coding_transcript_exon	Exon 7 of 21
	CDH23	ENST00000642965.1		n.*1565C>T		non_coding_transcript_exon	Exon 10 of 25	ENSP00000495222.1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152204 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00487

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00255 AC: 539 AN: 210966 AF XY: 0.00249

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.000808

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000666

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00335

GnomAD4 exome AF: 0.00371 AC: 5351 AN: 1440962 Hom.: 15 Cov.: 34 AF XY: 0.00362 AC XY: 2591 AN XY: 714960

African (AFR) AF: 0.000547 AC: 18 AN: 32906

American (AMR) AF: 0.000762 AC: 32 AN: 42002

Ashkenazi Jewish (ASJ) AF: 0.00382 AC: 98 AN: 25672

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38472

South Asian (SAS) AF: 0.000552 AC: 46 AN: 83352

European-Finnish (FIN) AF: 0.000617 AC: 32 AN: 51834

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.00449 AC: 4940 AN: 1101382

Other (OTH) AF: 0.00307 AC: 183 AN: 59592

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152322 Hom.: 3 Cov.: 31 AF XY: 0.00255 AC XY: 190 AN XY: 74488

African (AFR) AF: 0.000674 AC: 28 AN: 41564

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00487 AC: 331 AN: 68022

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00440 Hom.: 0

Bravo AF: 0.00270

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
-	-	5	not provided (5)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.8
DANN	Benign	0.45
PhyloP100		-3.4
Mutation Taster		=99/1	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: rs111033483; hg19: chr10-73563027; COSMIC: COSV56460930;