rs77821631

Positions:

• chr10-71712808-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.3364T>G​(p.Leu1122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,611,752 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 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 0.0068 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (9 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.56

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]

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

CDH23 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 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=0.005255878).
• BP6: Variant 10-71712808-T-G is Benign according to our data. Variant chr10-71712808-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45917.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00677 (1032/152350) while in subpopulation AFR AF= 0.0236 (980/41598). AF 95% confidence interval is 0.0223. There are 15 homozygotes in gnomad4. There are 475 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3364T>G	p.Leu1122Val	missense_variant	28/70	ENST00000224721.12	NP_071407.4
C10orf105	NM_001164375.3	c.*3128A>C		3_prime_UTR_variant	2/2	ENST00000441508.4	NP_001157847.1
CDH23	NM_001171930.2	c.3364T>G	p.Leu1122Val	missense_variant	28/32		NP_001165401.1
C10orf105	NM_001168390.2	c.*3128A>C		3_prime_UTR_variant	2/2		NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3364T>G	p.Leu1122Val	missense_variant	28/70	5	NM_022124.6	ENSP00000224721.9
C10orf105	ENST00000441508.4	c.*3128A>C		3_prime_UTR_variant	2/2	1	NM_001164375.3	ENSP00000403151.2

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1027 AN: 152232 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00168 AC: 409 AN: 242938 Hom.: 8 AF XY: 0.00115 AC XY: 152 AN XY: 132348

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.000998

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000845

GnomAD4 exome AF: 0.000662 AC: 966 AN: 1459402 Hom.: 9 Cov.: 31 AF XY: 0.000517 AC XY: 375 AN XY: 725778

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000933

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00677 AC: 1032 AN: 152350 Hom.: 15 Cov.: 33 AF XY: 0.00638 AC XY: 475 AN XY: 74502

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00143 Hom.: 3

Bravo AF: 0.00711

ESP6500AA AF: 0.0212 AC: 86

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00206 AC: 249

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2019	- -

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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2010

Leu1122Val in exon 28 of CDH23: This variant has been reported in 5/50 (10%) of control chromosomes from the Black population in dbSNP (rs77821631). In addition , this residue is not highly conserved across species. Of note, most other speci es have a valine at this position. In summary, this variant is not expected to h ave clinical significance. -

Usher syndrome type 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 03, 2019

- -

Usher syndrome type 1D Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.9
DANN	Benign	0.89
DEOGEN2	Benign	0.0070	T;T;T;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.45	T;T;T;T;T
MetaRNN	Benign	0.0053	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	.;.;N;.;.
PrimateAI	Benign	0.41	T
REVEL	Benign	0.064
Sift4G	Benign	1.0	T;T;.;T;.
Polyphen		0.0	.;.;B;.;.
Vest4		0.18
MVP		0.76
ClinPred		0.0035	T
GERP RS		4.9
Varity_R		0.059
gMVP		0.26

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: rs77821631; hg19: chr10-73472565;