rs149073355

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022124.6(CDH23):​c.3845A>G​(p.Asn1282Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,613,988 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0053 ( 21 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

1
7
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 7.22
Variant links:
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]
C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.012104154).
BP6
Variant 10-71732116-A-G is Benign according to our data. Variant chr10-71732116-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45931.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=3}. Variant chr10-71732116-A-G is described in Lovd as [Benign]. Variant chr10-71732116-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00529 (7726/1461702) while in subpopulation NFE AF= 0.00647 (7192/1111866). AF 95% confidence interval is 0.00634. There are 21 homozygotes in gnomad4_exome. There are 3668 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 21 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH23NM_022124.6 linkuse as main transcriptc.3845A>G p.Asn1282Ser missense_variant 32/70 ENST00000224721.12 NP_071407.4 Q9H251-1Q6P152
CDH23NM_001171930.2 linkuse as main transcriptc.3845A>G p.Asn1282Ser missense_variant 32/32 NP_001165401.1 Q9H251A0A087WYR8Q6P152
C10orf105NM_001168390.2 linkuse as main transcriptc.-6+5612T>C intron_variant NP_001161862.1 Q8TEF2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkuse as main transcriptc.3845A>G p.Asn1282Ser missense_variant 32/705 NM_022124.6 ENSP00000224721.9 Q9H251-1

Frequencies

GnomAD3 genomes
AF:
0.00333
AC:
507
AN:
152168
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00118
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00207
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00585
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00293
AC:
731
AN:
249260
Hom.:
1
AF XY:
0.00296
AC XY:
400
AN XY:
135236
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.00136
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00200
Gnomad NFE exome
AF:
0.00532
Gnomad OTH exome
AF:
0.00330
GnomAD4 exome
AF:
0.00529
AC:
7726
AN:
1461702
Hom.:
21
Cov.:
31
AF XY:
0.00504
AC XY:
3668
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.000986
Gnomad4 AMR exome
AF:
0.00143
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00257
Gnomad4 NFE exome
AF:
0.00647
Gnomad4 OTH exome
AF:
0.00485
GnomAD4 genome
AF:
0.00333
AC:
507
AN:
152286
Hom.:
1
Cov.:
32
AF XY:
0.00287
AC XY:
214
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00118
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00207
Gnomad4 NFE
AF:
0.00585
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00513
Hom.:
5
Bravo
AF:
0.00332
TwinsUK
AF:
0.00728
AC:
27
ALSPAC
AF:
0.00701
AC:
27
ESP6500AA
AF:
0.000933
AC:
4
ESP6500EA
AF:
0.00473
AC:
40
ExAC
AF:
0.00281
AC:
340
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00523
EpiControl
AF:
0.00522

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 23, 2021In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18429043, 26969326, 24729539, 32707200) -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024CDH23: BS1 -
not specified Benign:3
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 02, 2014Asn1282Ser in CDH23: This variant is not expected to have clinical significance because it has been identified in 0.5% (40/8452) of European American chromosome s and 0.01% (4/4286) African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS, rs149073355, Oshima 2008). -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 20, 2015- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 17, 2022Variant summary: CDH23 c.3845A>G (p.Asn1282Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 249260 control chromosomes, predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing Usher Syndrome phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -
Usher syndrome type 1D Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Meniere disease Uncertain:1
Uncertain significance, criteria provided, single submittercase-controlOtology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)Jun 21, 2021Digenic inheritance along with NM_000260.4:c.1007G>A(MYO7A) -
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Usher syndrome type 1 Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Jan 01, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.019
T;T;T;T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.012
T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.20
.;.;N;.
PrimateAI
Uncertain
0.61
T
REVEL
Uncertain
0.34
Sift4G
Uncertain
0.040
D;D;.;D
Polyphen
0.93
.;.;P;.
Vest4
0.76
MVP
0.68
ClinPred
0.046
T
GERP RS
4.8
Varity_R
0.30
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149073355; hg19: chr10-73491873; API