10-71809992-C-T

Variant names:

• chr10-71809992-C-T
• rs11000009
• NM_022124.6:c.8895C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.8895C>T​(p.Pro2965Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,612,096 control chromosomes in the GnomAD database, including 11,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2965P) has been classified as Likely benign. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.11 (1003 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10793 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -5.42
• Publications: 9 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

LOC124902446 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 10-71809992-C-T is Benign according to our data. Variant chr10-71809992-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 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.8895C>T	p.Pro2965Pro	synonymous	Exon 61 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.2175C>T	p.Pro725Pro	synonymous	Exon 14 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.2175C>T	p.Pro725Pro	synonymous	Exon 14 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.8895C>T	p.Pro2965Pro	synonymous	Exon 61 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.2431C>T		non_coding_transcript_exon	Exon 13 of 21
	CDH23	ENST00000642965.1		n.*2738C>T		non_coding_transcript_exon	Exon 16 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16641 AN: 152108 Hom.: 1003 Cov.: 32

Gnomad AFR AF: 0.0957

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0905

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.00481

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0944

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.111 AC: 27274 AN: 246734 AF XY: 0.116

Gnomad AFR exome AF: 0.0977

Gnomad AMR exome AF: 0.0636

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.00340

Gnomad FIN exome AF: 0.0962

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.116 AC: 169745 AN: 1459870 Hom.: 10793 Cov.: 33 AF XY: 0.119 AC XY: 86298 AN XY: 726194

African (AFR) AF: 0.0946 AC: 3167 AN: 33480

American (AMR) AF: 0.0664 AC: 2971 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 5023 AN: 26136

East Asian (EAS) AF: 0.00229 AC: 91 AN: 39700

South Asian (SAS) AF: 0.137 AC: 11791 AN: 86258

European-Finnish (FIN) AF: 0.0942 AC: 4863 AN: 51616

Middle Eastern (MID) AF: 0.225 AC: 1295 AN: 5768

European-Non Finnish (NFE) AF: 0.120 AC: 133424 AN: 1111836

Other (OTH) AF: 0.118 AC: 7120 AN: 60352

GnomAD4 genome AF: 0.109 AC: 16640 AN: 152226 Hom.: 1003 Cov.: 32 AF XY: 0.108 AC XY: 8033 AN XY: 74424

African (AFR) AF: 0.0955 AC: 3967 AN: 41524

American (AMR) AF: 0.0903 AC: 1383 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 654 AN: 3472

East Asian (EAS) AF: 0.00482 AC: 25 AN: 5184

South Asian (SAS) AF: 0.124 AC: 598 AN: 4818

European-Finnish (FIN) AF: 0.0944 AC: 1000 AN: 10596

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.128 AC: 8693 AN: 68010

Other (OTH) AF: 0.120 AC: 253 AN: 2110

Alfa AF: 0.124 Hom.: 538

Bravo AF: 0.106

Asia WGS AF: 0.0520 AC: 182 AN: 3478

EpiCase AF: 0.139

EpiControl AF: 0.135

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (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	-0.63
CADD	Benign	1.9
DANN	Benign	0.77
PhyloP100		-5.4
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11000009; hg19: chr10-73569749;