10-71397276-CCGAGGCGAGG-CCGAGGCGAGGCGAGG

Variant names:

• chr10-71397276-C-CCGAGG
• rs71012280
• NM_022124.6:c.-35_-31dupAGGCG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.-35_-31dupAGGCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13441 hom., cov: 0)
  • Exomes 𝑓: 0.40 (2201 hom.)
• Consequence: CDH23 NM_022124.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0300
• 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, 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 -16 ACMG points.

• BP6: Variant 10-71397276-C-CCGAGG is Benign according to our data. Variant chr10-71397276-C-CCGAGG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 300394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 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.-35_-31dupAGGCG		5_prime_UTR	Exon 1 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.-35_-31dupAGGCG		5_prime_UTR	Exon 1 of 32	NP_001165401.1
	CDH23	NM_001171931.2		c.-35_-31dupAGGCG		5_prime_UTR	Exon 1 of 26	NP_001165402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.-35_-31dupAGGCG		5_prime_UTR	Exon 1 of 70	ENSP00000224721.9
	CDH23	ENST00000644511.1		c.101_105dupAGGCG	p.Arg38GlyfsTer12	frameshift	Exon 1 of 4	ENSP00000495691.1
	CDH23	ENST00000616684.4	TSL:5	c.-35_-31dupAGGCG		5_prime_UTR	Exon 1 of 32	ENSP00000482036.2

Frequencies

GnomAD3 genomes AF: 0.379 AC: 56853 AN: 150148 Hom.: 13447 Cov.: 0

Gnomad AFR AF: 0.0937

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.379

GnomAD2 exomes AF: 0.394 AC: 97 AN: 246 AF XY: 0.387

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.400 AC: 8999 AN: 22518 Hom.: 2201 Cov.: 0 AF XY: 0.391 AC XY: 5554 AN XY: 14208

African (AFR) AF: 0.117 AC: 18 AN: 154

American (AMR) AF: 0.286 AC: 16 AN: 56

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 120 AN: 322

East Asian (EAS) AF: 0.417 AC: 65 AN: 156

South Asian (SAS) AF: 0.332 AC: 2101 AN: 6334

European-Finnish (FIN) AF: 0.441 AC: 561 AN: 1272

Middle Eastern (MID) AF: 0.240 AC: 124 AN: 516

European-Non Finnish (NFE) AF: 0.442 AC: 5674 AN: 12828

Other (OTH) AF: 0.364 AC: 320 AN: 880

GnomAD4 genome AF: 0.378 AC: 56835 AN: 150254 Hom.: 13441 Cov.: 0 AF XY: 0.381 AC XY: 27901 AN XY: 73326

African (AFR) AF: 0.0936 AC: 3854 AN: 41190

American (AMR) AF: 0.378 AC: 5741 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1518 AN: 3452

East Asian (EAS) AF: 0.515 AC: 2510 AN: 4874

South Asian (SAS) AF: 0.406 AC: 1948 AN: 4796

European-Finnish (FIN) AF: 0.544 AC: 5569 AN: 10238

Middle Eastern (MID) AF: 0.286 AC: 83 AN: 290

European-Non Finnish (NFE) AF: 0.511 AC: 34379 AN: 67236

Other (OTH) AF: 0.377 AC: 789 AN: 2092

Alfa AF: 0.322 Hom.: 703

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CDH23-related disorder (1)
-	-	1	Hearing loss, autosomal recessive (1)
-	-	1	not specified (1)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.030
Mutation Taster		=159/41	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71012280; hg19: chr10-73157033; COSMIC: COSV54948680;