rs188098974

Positions:

• chr10-71705007-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_022124.6(CDH23):​c.2830A>G​(p.Ser944Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00102 in 1,612,704 control chromosomes in the GnomAD database, including 9 homozygotes. 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 0.00095 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 5.16

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01838386).
• BP6: Variant 10-71705007-A-G is Benign according to our data. Variant chr10-71705007-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45902.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4, Benign=2}. Variant chr10-71705007-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.2830A>G	p.Ser944Gly	missense_variant	25/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.2830A>G	p.Ser944Gly	missense_variant	25/32		NP_001165401.1
CDH23	NM_001171931.2	c.2830A>G	p.Ser944Gly	missense_variant	25/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.2830A>G	p.Ser944Gly	missense_variant	25/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 144 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00121 AC: 300 AN: 247458 Hom.: 3 AF XY: 0.00136 AC XY: 184 AN XY: 134924

Gnomad AFR exome AF: 0.0000653

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.00102 AC: 1497 AN: 1460550 Hom.: 7 Cov.: 32 AF XY: 0.00117 AC XY: 848 AN XY: 726570

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.00273

Gnomad4 NFE exome AF: 0.000908

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.000946 AC: 144 AN: 152154 Hom.: 2 Cov.: 32 AF XY: 0.000995 AC XY: 74 AN XY: 74394

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00133 Hom.: 1

Bravo AF: 0.000544

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000951 AC: 8

ExAC AF: 0.00134 AC: 162

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CDH23: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2021	This variant is associated with the following publications: (PMID: 18429043, 32707200) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2015	- -

Usher syndrome type 1D Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 20, 2015

p.Ser944Gly in exon 25 of CDH23: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (55/16450) of South Asian chr omosomes with two homozygotes and in 0.3% (18/6608) of Finnish chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs18 8098971). -

Usher syndrome type 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T;T;.;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T;T;T;T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.018	T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.
PrimateAI	Benign	0.39	T
REVEL	Benign	0.18
Sift4G	Uncertain	0.0040	D;T;.;T;D;.
Polyphen		0.014	.;.;B;.;.;.
Vest4		0.29
MVP		0.88
ClinPred		0.081	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.29

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

Other links and lift over

dbSNP: rs188098974; hg19: chr10-73464764;