10-71730553-G-A

Position:

chr10-71730553-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022124.6(CDH23):c.3664G>A(p.Ala1222Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0254 in 1,613,902 control chromosomes in the GnomAD database, including 621 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 44 hom., cov: 33)

Exomes 𝑓: 0.026 ( 577 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 6.61

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007181257).

BP6

Variant 10-71730553-G-A is Benign according to our data. Variant chr10-71730553-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71730553-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0203 (3096/152342) while in subpopulation NFE AF= 0.0282 (1917/68026). AF 95% confidence interval is 0.0271. There are 44 homozygotes in gnomad4. There are 1503 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 44 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDH23	NM_022124.6 linkuse as main transcript	c.3664G>A	p.Ala1222Thr	missense_variant	31/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2 linkuse as main transcript	c.3664G>A	p.Ala1222Thr	missense_variant	31/32		NP_001165401.1
C10orf105	NM_001168390.2 linkuse as main transcript	c.-6+7175C>T		intron_variant			NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.3664G>A	p.Ala1222Thr	missense_variant	31/70	5	NM_022124.6	ENSP00000224721	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0204

AC:

3098

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00569

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0278

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.0199

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0282

Gnomad OTH

AF:

0.0320

GnomAD3 exomes

AF:

0.0208

AC:

5187

AN:

248828

Hom.:

AF XY:

0.0217

AC XY:

2935

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.00434

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.0500

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0126

Gnomad FIN exome

AF:

0.0197

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0291

GnomAD4 exome

AF:

0.0260

AC:

37965

AN:

1461560

Hom.:

577

Cov.:

AF XY:

0.0258

AC XY:

18790

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00454

Gnomad4 AMR exome

AF:

0.0134

Gnomad4 ASJ exome

AF:

0.0548

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0128

Gnomad4 FIN exome

AF:

0.0194

Gnomad4 NFE exome

AF:

0.0286

Gnomad4 OTH exome

AF:

0.0270

GnomAD4 genome

AF:

0.0203

AC:

3096

AN:

152342

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1503

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00568

Gnomad4 AMR

AF:

0.0277

Gnomad4 ASJ

AF:

0.0493

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0120

Gnomad4 FIN

AF:

0.0199

Gnomad4 NFE

AF:

0.0282

Gnomad4 OTH

AF:

0.0317

Alfa

AF:

0.0273

Hom.:

106

Bravo

AF:

0.0210

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.00542

AC:

ESP6500EA

AF:

0.0334

AC:

280

ExAC

AF:

0.0207

AC:

2503

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0312

EpiControl

AF:

0.0308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Usher syndrome type 1D

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

T;T;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

T;T;T;T

MetaRNN

Benign

0.0072

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.82

.;.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

REVEL

Benign

0.18

Sift4G

Uncertain

0.028

D;D;.;D

Polyphen

0.89

.;.;P;.

Vest4

0.58

ClinPred

0.039

GERP RS

3.4

Varity_R

0.099

gMVP

0.39

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