10-71712805-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1

The NM_022124.6(CDH23):c.3361A>T(p.Ile1121Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,612,118 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 6.27

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 links:

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

C10orf105 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a domain Cadherin 11 (size 105) in uniprot entity CAD23_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_022124.6

BP4

Computational evidence support a benign effect (MetaRNN=0.013111502).

BP6

Variant 10-71712805-A-T is Benign according to our data. Variant chr10-71712805-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45916.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00129 (196/152374) while in subpopulation AFR AF= 0.0045 (187/41600). AF 95% confidence interval is 0.00397. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.3361A>T	p.Ile1121Phe	missense_variant	Exon 28 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
C10orf105	NM_001164375.3 link	c.*3131T>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000441508.4	NP_001157847.1	Q8TEF2
CDH23	NM_001171930.2 link	c.3361A>T	p.Ile1121Phe	missense_variant	Exon 28 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
C10orf105	NM_001168390.2 link	c.*3131T>A		3_prime_UTR_variant	Exon 2 of 2		NP_001161862.1	Q8TEF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.3361A>T	p.Ile1121Phe	missense_variant	Exon 28 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1
C10orf105	ENST00000441508 link	c.*3131T>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_001164375.3	ENSP00000403151.2		Q8TEF2

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00444

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000332

AC:

AN:

243680

Hom.:

AF XY:

0.000218

AC XY:

AN XY:

132766

show subpopulations

Gnomad AFR exome

AF:

0.00494

Gnomad AMR exome

AF:

0.000205

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

188

AN:

1459744

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

725998

show subpopulations

Gnomad4 AFR exome

AF:

0.00445

Gnomad4 AMR exome

AF:

0.000247

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

AF:

0.00129

AC:

196

AN:

152374

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.00450

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.00151

ESP6500AA

AF:

0.00416

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000397

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Aug 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile1121Phe variant (rs200542052) has not been reported in the medical literature. This variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.46% in the African population (identified in 108 out of 23,580 chromosomes; 0 homozygotes), and is listed in ClinVar with conflicting interpretations of pathogenicity (benign/uncertain significance; Variant ID: 45916). The isoleucine at codon 1121 is highly conserved considering 12 species up to zebrafish (Alamut software v2.9.0), and computational analyses suggest that this variant affects the CDH23 protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). While the frequency of this variant in the African population suggests that it is a benign polymorphism, the available evidence is insufficient to classify the clinical significance with certainty. -

Retinal dystrophy

Uncertain:1

Mar 20, 2018

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jul 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ile1121Phe in exon 28 of CDH23: This variant is not expected to have clinical significance because it is has been identified in 0.6% (44/7874) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs200542052). -

Usher syndrome type 1

Benign:1

Apr 13, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;T;T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

D;D;D;D;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.7

.;.;L;.;.

PrimateAI

Uncertain

0.52

REVEL

Uncertain

0.31

Sift4G

Uncertain

0.0030

D;D;.;D;.

Polyphen

0.85

.;.;P;.;.

Vest4

0.93

MVP

0.88

ClinPred

0.092

GERP RS

4.9

Varity_R

0.34

gMVP

0.73

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over