10-71777726-C-T

Position:

• chr10-71777726-C-T

Variant summary

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

The NM_022124.6(CDH23):​c.4892C>T​(p.Ala1631Val) variant causes a missense change. The variant allele was found at a frequency of 0.000513 in 1,613,534 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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. A1631T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:4
• Conservation: PhyloP100: 4.92

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=0.0092161).
• BP6: Variant 10-71777726-C-T is Benign according to our data. Variant chr10-71777726-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178305.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=6}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.4892C>T	p.Ala1631Val	missense_variant	39/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.4892C>T	p.Ala1631Val	missense_variant	39/70	5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000747 AC: 185 AN: 247786 Hom.: 2 AF XY: 0.000973 AC XY: 131 AN XY: 134612

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00495

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000528 AC: 771 AN: 1461254 Hom.: 3 Cov.: 32 AF XY: 0.000659 AC XY: 479 AN XY: 726882

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00444

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000296

Gnomad4 OTH exome AF: 0.000779

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74456

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000356 AC: 3

ExAC AF: 0.000851 AC: 103

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2019	This variant is associated with the following publications: (PMID: 30303587, 23804846) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CDH23: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 22, 2021	- -

Usher syndrome type 1D Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

CDH23-related disorder Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 10, 2023	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2014

Variant classified as Uncertain Significance - Favor Benign. The Ala1631Val vari ant in CDH23 has been reported in one individual with hearing loss; however, thi s individual did not have a second variant in the CDH23 gene (Shearer 2013). Thi s variant was also identified in 0.04% (3/8432) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The alanine (Ala) residue at position 1631 is not conserved across several species w ith Gorilla having valine (Val) at this position, suggesting that the variant ma y be tolerated. However, this information is not sufficient to rule out pathogen icity. In summary, the clinical significance of this variant cannot be determine d with certainty; however based upon the conservation data, we would lean toward s a more likely benign role. -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.070
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.4	.;L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
REVEL	Benign	0.098
Sift4G	Uncertain	0.027	D;.
Polyphen		0.0070	.;B
Vest4		0.36
MVP		0.58
ClinPred		0.046	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs370762269; hg19: chr10-73537483; COSMIC: COSV99822798; COSMIC: COSV99822798;