chr10-71812624-GTCAGGCA-G

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 NM_022124.6(CDH23):​c.9510+19_9510+25delGGCATCA 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). The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (85 hom.)
• Consequence: CDH23 NM_022124.6 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
• 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

LOC124902446 (HGNC:):

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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: 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.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	Q9H251-7
	CDH23	NM_001171934.1		c.2790+19_2790+25delGGCATCA		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.9510+16_9510+22delTCAGGCA		intron	N/A	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.3046+16_3046+22delTCAGGCA		intron	N/A
	CDH23	ENST00000642965.1		n.*3353+16_*3353+22delTCAGGCA		intron	N/A	ENSP00000495222.1	A0A2R8Y6D5

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

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;