10-71815116-C-T

Variant names:

• chr10-71815116-C-T
• rs55717455
• NM_022124.6:c.9903C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.9903C>T​(p.Pro3301Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,611,154 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P3301P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: -7.03
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 10-71815116-C-T is Benign according to our data. Variant chr10-71815116-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46081.
• BP7: Synonymous conserved (PhyloP=-7.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0034 (518/152400) while in subpopulation AFR AF = 0.00834 (347/41602). AF 95% confidence interval is 0.00762. There are 5 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.9903C>T	p.Pro3301Pro	synonymous	Exon 70 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.3183C>T	p.Pro1061Pro	synonymous	Exon 23 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.3078C>T	p.Pro1026Pro	synonymous	Exon 22 of 22	NP_001165405.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9903C>T	p.Pro3301Pro	synonymous	Exon 70 of 70	ENSP00000224721.9
	CDH23	ENST00000475158.1	TSL:1	n.3334C>T		non_coding_transcript_exon	Exon 21 of 21
	CDH23	ENST00000642965.1		n.*3746C>T		non_coding_transcript_exon	Exon 25 of 25	ENSP00000495222.1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 508 AN: 152282 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.00812

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00179 AC: 433 AN: 241344 AF XY: 0.00165

Gnomad AFR exome AF: 0.00835

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00112

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000666

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00305

GnomAD4 exome AF: 0.00113 AC: 1653 AN: 1458754 Hom.: 4 Cov.: 31 AF XY: 0.00115 AC XY: 833 AN XY: 725578

African (AFR) AF: 0.00808 AC: 270 AN: 33436

American (AMR) AF: 0.00356 AC: 158 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26044

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85902

European-Finnish (FIN) AF: 0.000785 AC: 41 AN: 52224

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5764

European-Non Finnish (NFE) AF: 0.000876 AC: 973 AN: 1111036

Other (OTH) AF: 0.00236 AC: 142 AN: 60284

GnomAD4 genome AF: 0.00340 AC: 518 AN: 152400 Hom.: 5 Cov.: 34 AF XY: 0.00337 AC XY: 251 AN XY: 74532

African (AFR) AF: 0.00834 AC: 347 AN: 41602

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 68044

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.00376

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Atypical Gaucher Disease (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	CDH23-related disorder (1)
-	-	1	Combined PSAP deficiency (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	Metachromatic leukodystrophy (1)
-	-	1	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.8
DANN	Benign	0.91
PhyloP100		-7.0
Mutation Taster		=93/7	polymorphism

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: rs55717455; hg19: chr10-73574873;