NM_022124.6:c.-258G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022124.6(CDH23):​c.-258G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 155,680 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 124 hom., cov: 30)
Exomes 𝑓: 0.033 ( 4 hom. )

Consequence

CDH23
NM_022124.6 5_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.32

Publications

3 publications found
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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 10-71397066-G-A is Benign according to our data. Variant chr10-71397066-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 300389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH23NM_022124.6 linkc.-258G>A 5_prime_UTR_variant Exon 1 of 70 ENST00000224721.12 NP_071407.4 Q9H251-1Q6P152

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkc.-258G>A 5_prime_UTR_variant Exon 1 of 70 5 NM_022124.6 ENSP00000224721.9 Q9H251-1

Frequencies

GnomAD3 genomes
AF:
0.0380
AC:
5745
AN:
151274
Hom.:
125
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0597
Gnomad AMI
AF:
0.0430
Gnomad AMR
AF:
0.0304
Gnomad ASJ
AF:
0.0369
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0434
Gnomad FIN
AF:
0.0191
Gnomad MID
AF:
0.0645
Gnomad NFE
AF:
0.0315
Gnomad OTH
AF:
0.0448
GnomAD4 exome
AF:
0.0328
AC:
141
AN:
4300
Hom.:
4
Cov.:
0
AF XY:
0.0367
AC XY:
107
AN XY:
2912
show subpopulations
African (AFR)
AF:
0.0500
AC:
1
AN:
20
American (AMR)
AF:
0.0417
AC:
1
AN:
24
Ashkenazi Jewish (ASJ)
AF:
0.0385
AC:
2
AN:
52
East Asian (EAS)
AF:
0.00
AC:
0
AN:
70
South Asian (SAS)
AF:
0.0500
AC:
35
AN:
700
European-Finnish (FIN)
AF:
0.0139
AC:
2
AN:
144
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
18
European-Non Finnish (NFE)
AF:
0.0309
AC:
96
AN:
3102
Other (OTH)
AF:
0.0235
AC:
4
AN:
170
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
5
10
16
21
26
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0379
AC:
5743
AN:
151380
Hom.:
124
Cov.:
30
AF XY:
0.0373
AC XY:
2756
AN XY:
73968
show subpopulations
African (AFR)
AF:
0.0595
AC:
2464
AN:
41384
American (AMR)
AF:
0.0304
AC:
463
AN:
15242
Ashkenazi Jewish (ASJ)
AF:
0.0369
AC:
128
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5104
South Asian (SAS)
AF:
0.0431
AC:
207
AN:
4808
European-Finnish (FIN)
AF:
0.0191
AC:
198
AN:
10390
Middle Eastern (MID)
AF:
0.0694
AC:
20
AN:
288
European-Non Finnish (NFE)
AF:
0.0315
AC:
2131
AN:
67692
Other (OTH)
AF:
0.0443
AC:
93
AN:
2098
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
279
558
837
1116
1395
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
66
132
198
264
330
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0339
Hom.:
9
Bravo
AF:
0.0402

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

May 12, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Usher syndrome type 1D Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 12 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
4.7
DANN
Benign
0.91
PhyloP100
-1.3
PromoterAI
-0.020
Neutral
Mutation Taster
=299/1
polymorphism

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

Other links and lift over

dbSNP: rs139742443; hg19: chr10-73156823; API