chr10-71439832-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_022124.6(CDH23):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000128 in 1,563,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CDH23
NM_022124.6 start_lost

Scores

5
4
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.16

Publications

4 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: Pathogenic. The variant received 10 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 60 codons. Genomic position: 71510114. Lost 0.018 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH23NM_022124.6 linkc.1A>G p.Met1? start_lost Exon 2 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.1A>G p.Met1? start_lost Exon 2 of 70 5 NM_022124.6 ENSP00000224721.9 Q9H251-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
7.09e-7
AC:
1
AN:
1411316
Hom.:
0
Cov.:
31
AF XY:
0.00000143
AC XY:
1
AN XY:
697312
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32180
American (AMR)
AF:
0.00
AC:
0
AN:
37370
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25318
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37054
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80028
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50260
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5704
European-Non Finnish (NFE)
AF:
9.22e-7
AC:
1
AN:
1084918
Other (OTH)
AF:
0.00
AC:
0
AN:
58484
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74314
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41416
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0094
T;T;T;.;.;T;.
Eigen
Benign
0.022
Eigen_PC
Benign
0.068
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D;D
MetaSVM
Benign
-0.70
T
PhyloP100
4.2
PROVEAN
Benign
-0.73
N;.;N;.;N;.;.
REVEL
Uncertain
0.31
Sift
Benign
0.031
D;.;D;.;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;.
Polyphen
0.32, 0.45
.;.;B;B;.;.;.
Vest4
0.91
MutPred
0.67
Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);
MVP
0.80
ClinPred
0.98
D
GERP RS
4.6
PromoterAI
-0.022
Neutral
Varity_R
0.38
gMVP
0.32
Mutation Taster
=7/193
disease causing

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

Publications

Other links and lift over

dbSNP: rs1298721050; hg19: chr10-73199589; API