rs397517307

Positions:

• chr10-71675134-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_022124.6(CDH23):​c.1472C>T​(p.Thr491Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,000 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (1 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.97

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a domain Cadherin 5 (size 100) in uniprot entity CAD23_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_022124.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.06233692).
• BP6: Variant 10-71675134-C-T is Benign according to our data. Variant chr10-71675134-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45873.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1472C>T	p.Thr491Ile	missense_variant	15/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1472C>T	p.Thr491Ile	missense_variant	15/32		NP_001165401.1
CDH23	NM_001171931.2	c.1472C>T	p.Thr491Ile	missense_variant	15/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1472C>T	p.Thr491Ile	missense_variant	15/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 249242 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000766 AC: 112 AN: 1461664 Hom.: 1 Cov.: 31 AF XY: 0.000100 AC XY: 73 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1D Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 23, 2012

Thr491Ile in exon 15 of CDH23: This variant is not expected to have clinical sig nificance due to a lack of conservation of the amino acid site across species, i ncluding mammals. Of note, the kangaroo rat has an Ile at this position, despit e high nearby amino acid conservation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T;T;.;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.062	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.45	.;.;N;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	.;.;.;.;.;N
REVEL	Benign	0.046
Sift	Benign	0.034	.;.;.;.;.;D
Sift4G	Uncertain	0.051	T;D;.;T;T;.
Polyphen		0.0050	.;.;B;.;.;.
Vest4		0.23
MutPred		0.41		Loss of disorder (P = 0.0576);Loss of disorder (P = 0.0576);Loss of disorder (P = 0.0576);Loss of disorder (P = 0.0576);Loss of disorder (P = 0.0576);Loss of disorder (P = 0.0576);
MVP		0.68
ClinPred		0.066	T
GERP RS		2.6
Varity_R		0.083
gMVP		0.36

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: rs397517307; hg19: chr10-73434891;