rs369395479

Positions:

• chr10-71811550-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.9238G>A​(p.Ala3080Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000695 in 1,613,840 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (12 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 5.80

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008137375).
• BP6: Variant 10-71811550-G-A is Benign according to our data. Variant chr10-71811550-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226501.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr10-71811550-G-A is described in Lovd as [Benign]. Variant chr10-71811550-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000381 (58/152166) while in subpopulation SAS AF= 0.00851 (41/4818). AF 95% confidence interval is 0.00645. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.9238G>A	p.Ala3080Thr	missense_variant	64/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.2518G>A	p.Ala840Thr	missense_variant	17/23		NP_001165404.1
CDH23	NM_001171934.1	c.2518G>A	p.Ala840Thr	missense_variant	17/22		NP_001165405.1
LOC124902446	XR_007062185.1	n.1209C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.9238G>A	p.Ala3080Thr	missense_variant	64/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152048 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00137 AC: 341 AN: 249144 Hom.: 4 AF XY: 0.00179 AC XY: 242 AN XY: 135184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000556

Gnomad SAS exome AF: 0.00974

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000728 AC: 1064 AN: 1461674 Hom.: 12 Cov.: 32 AF XY: 0.000983 AC XY: 715 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.00954

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 31 AN XY: 74382

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00851

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 03, 2016	c.9238G>A (p.Ala3080Thr) in exon 64 of CDH23: This variant is not expected to ha ve clinical significance because it has been identified in 1% (163/16512) of Sou th Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs369395479). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2022	Variant summary: CDH23 c.9238G>A (p.Ala3080Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 253168 control chromosomes (gnomAD, publications), predominantly at a frequency of 0.0097 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing an Usher Syndrome phenotype (0.0032), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.9238G>A has been reported in the literature on individuals affected with autosomal recessive non-syndromic hearing loss (Sloan-Heggen_2016), however this report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: six have classified the variant as benign and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CDH23: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2019	This variant is associated with the following publications: (PMID: 26969326, 24767429, 22135276) -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 20, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 20, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T;T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T;T;T;T
MetaRNN	Benign	0.0081	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	.;L;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	.;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.32	.;.;.;T
Sift4G	Benign	0.11	T;.;T;T
Polyphen		0.016	.;B;.;.
Vest4		0.45
MVP		0.78
MPC		0.17
ClinPred		0.039	T
GERP RS		4.5
Varity_R		0.052
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs369395479; hg19: chr10-73571307;