NM_022124.6:c.7055-16A>G

Variant names:

• chr10-71799095-A-G
• rs4747193
• NM_022124.6:c.7055-16A>G

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.7055-16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,600,438 control chromosomes in the GnomAD database, including 81,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9720 hom., cov: 32)
  • Exomes 𝑓: 0.31 (71983 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.18
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-71799095-A-G is Benign according to our data. Variant chr10-71799095-A-G is described in ClinVar as Benign. ClinVar VariationId is 46025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.597 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.7055-16A>G		intron	N/A	NP_071407.4
	CDH23	NM_001171933.1		c.335-16A>G		intron	N/A	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.335-16A>G		intron	N/A	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.7055-16A>G		intron	N/A	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.591-16A>G		intron	N/A
	CDH23	ENST00000642965.1		n.*898-16A>G		intron	N/A	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52480 AN: 151946 Hom.: 9700 Cov.: 32

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.321

GnomAD2 exomes AF: 0.341 AC: 83505 AN: 244856 AF XY: 0.326

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.305 AC: 441809 AN: 1448374 Hom.: 71983 Cov.: 33 AF XY: 0.301 AC XY: 216473 AN XY: 718976

African (AFR) AF: 0.450 AC: 14935 AN: 33188

American (AMR) AF: 0.434 AC: 19241 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6005 AN: 25658

East Asian (EAS) AF: 0.664 AC: 26235 AN: 39504

South Asian (SAS) AF: 0.266 AC: 22816 AN: 85712

European-Finnish (FIN) AF: 0.346 AC: 18358 AN: 53058

Middle Eastern (MID) AF: 0.203 AC: 1155 AN: 5702

European-Non Finnish (NFE) AF: 0.285 AC: 314328 AN: 1101466

Other (OTH) AF: 0.313 AC: 18736 AN: 59766

GnomAD4 genome AF: 0.345 AC: 52537 AN: 152064 Hom.: 9720 Cov.: 32 AF XY: 0.348 AC XY: 25861 AN XY: 74344

African (AFR) AF: 0.444 AC: 18410 AN: 41456

American (AMR) AF: 0.355 AC: 5433 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 791 AN: 3472

East Asian (EAS) AF: 0.615 AC: 3182 AN: 5172

South Asian (SAS) AF: 0.280 AC: 1350 AN: 4816

European-Finnish (FIN) AF: 0.346 AC: 3658 AN: 10576

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.274 AC: 18631 AN: 67966

Other (OTH) AF: 0.319 AC: 673 AN: 2112

Alfa AF: 0.299 Hom.: 1340

Bravo AF: 0.358

Asia WGS AF: 0.412 AC: 1434 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types (1)
-	-	1	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.072
DANN	Benign	0.28
PhyloP100		-1.2
Mutation Taster		=98/2	polymorphism (auto)

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: rs4747193; hg19: chr10-73558852;