rs483353053

Variant names:

• chr10-71812624-GTCAGGCA-G
• rs149704197
• NM_022124.6:c.9510+19_9510+25delGGCATCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000224721.12(CDH23):​c.9510+16_9510+22delTCAGGCA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,613,816 control chromosomes in the GnomAD database, including 178 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (85 hom.)
• Consequence: CDH23 ENST00000224721.12 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.0120
• 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

LOC124902446 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 10-71812624-GTCAGGCA-G is Benign according to our data. Variant chr10-71812624-GTCAGGCA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133306.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000224721.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.9510+19_9510+25delGGCATCA		intron	N/A	NP_071407.4
	CDH23	NM_001171933.1		c.2790+19_2790+25delGGCATCA		intron	N/A	NP_001165404.1
	CDH23	NM_001171934.1		c.2790+19_2790+25delGGCATCA		intron	N/A	NP_001165405.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9510+16_9510+22delTCAGGCA		intron	N/A	ENSP00000224721.9
	CDH23	ENST00000398788.4	TSL:1	c.2790+16_2790+22delTCAGGCA		intron	N/A	ENSP00000381768.3
	CDH23	ENST00000619887.4	TSL:1	c.2790+16_2790+22delTCAGGCA		intron	N/A	ENSP00000478374.1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2994 AN: 152242 Hom.: 93 Cov.: 33

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00889

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00507 AC: 1261 AN: 248640 AF XY: 0.00403

Gnomad AFR exome AF: 0.0683

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000444

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00206 AC: 3014 AN: 1461456 Hom.: 85 AF XY: 0.00183 AC XY: 1327 AN XY: 727036

African (AFR) AF: 0.0684 AC: 2289 AN: 33476

American (AMR) AF: 0.00411 AC: 184 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.000225 AC: 250 AN: 1111854

Other (OTH) AF: 0.00427 AC: 258 AN: 60366

GnomAD4 genome AF: 0.0197 AC: 2995 AN: 152360 Hom.: 93 Cov.: 33 AF XY: 0.0193 AC XY: 1440 AN XY: 74514

African (AFR) AF: 0.0675 AC: 2805 AN: 41562

American (AMR) AF: 0.00888 AC: 136 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68040

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00995 Hom.: 9

Bravo AF: 0.0222

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Atypical Gaucher Disease (1)
-	-	1	Combined PSAP deficiency (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	Metachromatic leukodystrophy (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.012
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs149704197; hg19: chr10-73572381;