rs143993990

chr10-71784337-G-Achr10-71784337-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_022124.6(CDH23):c.5419G>A(p.Val1807Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,613,942 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. V1807V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (8 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.28

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007494718).
• BP6: Variant 10-71784337-G-A is Benign according to our data. Variant chr10-71784337-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71784337-G-A is described in Lovd as [Likely_benign]. Variant chr10-71784337-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00251 (382/152332) while in subpopulation AFR AF= 0.00842 (350/41568). AF 95% confidence interval is 0.00769. There are 0 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.5419G>A	p.Val1807Met	missense_variant	42/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.5419G>A	p.Val1807Met	missense_variant	42/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00842

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000690 AC: 172 AN: 249164 Hom.: 1 AF XY: 0.000636 AC XY: 86 AN XY: 135184

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000389 AC: 568 AN: 1461610 Hom.: 8 Cov.: 32 AF XY: 0.000393 AC XY: 286 AN XY: 727104

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00260 AC XY: 194 AN XY: 74498

Gnomad4 AFR AF: 0.00842

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.00283

ESP6500AA AF: 0.00724 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000794 AC: 96

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2020	This variant is associated with the following publications: (PMID: 22899989, 17850630, 25587757, 22443853) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 31, 2016

Val1807Met in Exon 42 of CDH23: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (72/9790) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs143993990). -

CDH23-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	0.034
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.062	T;.
Polyphen		0.23	.;B
Vest4		0.20
MVP		0.57
ClinPred		0.030	T
GERP RS		5.4
Varity_R		0.031
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143993990; hg19: chr10-73544094; COSMIC: COSV99821870;