rs41281302

Variant names:

• chr10-71439831-C-T
• rs41281302
• NM_022124.6:c.-1C>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.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,560,814 control chromosomes in the GnomAD database, including 2,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1120 hom., cov: 33)
  • Exomes 𝑓: 0.028 (1451 hom.)
• Consequence: CDH23 NM_022124.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.36
• 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: PanelApp Australia, 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: PanelApp Australia, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-71439831-C-T is Benign according to our data. Variant chr10-71439831-C-T is described in ClinVar as Benign. ClinVar VariationId is 162864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 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.-1C>T		5_prime_UTR	Exon 2 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.-1C>T		5_prime_UTR	Exon 2 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.-1C>T		5_prime_UTR	Exon 2 of 26	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.-1C>T		5_prime_UTR	Exon 2 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.-1C>T		5_prime_UTR	Exon 2 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.-1C>T		5_prime_UTR	Exon 2 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.0791 AC: 12030 AN: 152086 Hom.: 1109 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0677

GnomAD2 exomes AF: 0.0367 AC: 6339 AN: 172822 AF XY: 0.0347

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.000720

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0239

Gnomad OTH exome AF: 0.0383

GnomAD4 exome AF: 0.0283 AC: 39816 AN: 1408608 Hom.: 1451 Cov.: 31 AF XY: 0.0284 AC XY: 19766 AN XY: 695958

African (AFR) AF: 0.225 AC: 7157 AN: 31832

American (AMR) AF: 0.0259 AC: 966 AN: 37274

Ashkenazi Jewish (ASJ) AF: 0.0353 AC: 892 AN: 25286

East Asian (EAS) AF: 0.000189 AC: 7 AN: 36980

South Asian (SAS) AF: 0.0484 AC: 3864 AN: 79908

European-Finnish (FIN) AF: 0.0226 AC: 1134 AN: 50190

Middle Eastern (MID) AF: 0.0813 AC: 462 AN: 5686

European-Non Finnish (NFE) AF: 0.0213 AC: 23103 AN: 1083104

Other (OTH) AF: 0.0382 AC: 2231 AN: 58348

GnomAD4 genome AF: 0.0794 AC: 12084 AN: 152206 Hom.: 1120 Cov.: 33 AF XY: 0.0771 AC XY: 5736 AN XY: 74422

African (AFR) AF: 0.219 AC: 9093 AN: 41478

American (AMR) AF: 0.0407 AC: 623 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.0536 AC: 259 AN: 4830

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10624

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1599 AN: 68004

Other (OTH) AF: 0.0670 AC: 141 AN: 2106

Alfa AF: 0.0539 Hom.: 405

Bravo AF: 0.0858

Asia WGS AF: 0.0390 AC: 134 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.83
PhyloP100		1.4
PromoterAI		-0.046	Neutral
Mutation Taster		=275/25	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: rs41281302; hg19: chr10-73199588;