10-71397276-CCGAGGCGAGG-CCGAGG

Variant names:

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

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_-31delAGGCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 172,870 control chromosomes in the GnomAD database, including 1,393 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1313 hom., cov: 0)
  • Exomes 𝑓: 0.067 (80 hom.)
• Consequence: CDH23 NM_022124.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.67
• 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-CCGAGG-C is Benign according to our data. Variant chr10-71397276-CCGAGG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 300395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 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_-31delAGGCG		5_prime_UTR	Exon 1 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.-35_-31delAGGCG		5_prime_UTR	Exon 1 of 32	NP_001165401.1
	CDH23	NM_001171931.2		c.-35_-31delAGGCG		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_-31delAGGCG		5_prime_UTR	Exon 1 of 70	ENSP00000224721.9
	CDH23	ENST00000644511.1		c.101_105delAGGCG	p.Glu34AlafsTer23	frameshift	Exon 1 of 4	ENSP00000495691.1
	CDH23	ENST00000616684.4	TSL:5	c.-35_-31delAGGCG		5_prime_UTR	Exon 1 of 32	ENSP00000482036.2

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16378 AN: 150180 Hom.: 1304 Cov.: 0

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0437

Gnomad AMR AF: 0.0722

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0781

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0812

Gnomad MID AF: 0.0955

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.0528 AC: 13 AN: 246 AF XY: 0.0493

Gnomad NFE exome AF: 0.0513

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.0675 AC: 1524 AN: 22584 Hom.: 80 AF XY: 0.0692 AC XY: 986 AN XY: 14252

African (AFR) AF: 0.123 AC: 19 AN: 154

American (AMR) AF: 0.0714 AC: 4 AN: 56

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 21 AN: 322

East Asian (EAS) AF: 0.0833 AC: 13 AN: 156

South Asian (SAS) AF: 0.0917 AC: 582 AN: 6350

European-Finnish (FIN) AF: 0.0754 AC: 96 AN: 1274

Middle Eastern (MID) AF: 0.159 AC: 82 AN: 516

European-Non Finnish (NFE) AF: 0.0508 AC: 654 AN: 12876

Other (OTH) AF: 0.0602 AC: 53 AN: 880

GnomAD4 genome AF: 0.109 AC: 16417 AN: 150286 Hom.: 1313 Cov.: 0 AF XY: 0.109 AC XY: 7987 AN XY: 73344

African (AFR) AF: 0.230 AC: 9476 AN: 41168

American (AMR) AF: 0.0720 AC: 1094 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 270 AN: 3456

East Asian (EAS) AF: 0.0779 AC: 380 AN: 4876

South Asian (SAS) AF: 0.0957 AC: 459 AN: 4798

European-Finnish (FIN) AF: 0.0812 AC: 833 AN: 10256

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 290

European-Non Finnish (NFE) AF: 0.0537 AC: 3614 AN: 67262

Other (OTH) AF: 0.106 AC: 222 AN: 2094

Alfa AF: 0.0250 Hom.: 703

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=113/87	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;