chr10-71807995-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_022124.6(CDH23):c.8710G>T(p.Val2904Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,588,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2904I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.28

Publications

2 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

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04017073).

BP6

Variant 10-71807995-G-T is Benign according to our data. Variant chr10-71807995-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2153305.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.8710G>T	p.Val2904Phe	missense_variant	Exon 60 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171933.1 link	c.1990G>T	p.Val664Phe	missense_variant	Exon 13 of 23		NP_001165404.1	Q9H251-7
CDH23	NM_001171934.1 link	c.1990G>T	p.Val664Phe	missense_variant	Exon 13 of 22		NP_001165405.1	Q9H251-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.8710G>T	p.Val2904Phe	missense_variant	Exon 60 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152244

Hom.:

Cov.:

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:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000921

AC:

AN:

206328

AF XY:

0.0000990

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00126

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1436228

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

711934

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32958

American (AMR)

AF:

0.00

AC:

AN:

41136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25654

East Asian (EAS)

AF:

0.000260

AC:

AN:

38454

South Asian (SAS)

AF:

0.00

AC:

AN:

82418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000364

AC:

AN:

1098938

Other (OTH)

AF:

0.0000168

AC:

AN:

59400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00115

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000664

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8710G>T (p.V2904F) alteration is located in exon 60 (coding exon 59) of the CDH23 gene. This alteration results from a G to T substitution at nucleotide position 8710, causing the valine (V) at amino acid position 2904 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

T;T;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

.;L;.;.

PhyloP100

2.3

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.67

.;N;.;N

REVEL

Benign

0.22

Sift

Uncertain

0.0020

.;D;.;T

Sift4G

Uncertain

0.0040

D;.;D;D

Polyphen

0.97

.;D;.;.

Vest4

0.69

MVP

0.82

MPC

0.21

ClinPred

0.14

GERP RS

5.3

Varity_R

0.15

gMVP

0.64

Mutation Taster

=55/45

polymorphism

(source)

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

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chr10-71807995-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over