rs121908352

Positions:

• chr10-71785051-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_022124.6(CDH23):​c.5663T>C​(p.Phe1888Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.17

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 10-71785051-T-C is Pathogenic according to our data. Variant chr10-71785051-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4924.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.5663T>C	p.Phe1888Ser	missense_variant	43/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.5663T>C	p.Phe1888Ser	missense_variant	43/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461702 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 09, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 4924). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 15829536). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 1888 of the CDH23 protein (p.Phe1888Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. -

Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 14, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Uncertain	0.67	T
REVEL	Pathogenic	0.65
Sift4G	Pathogenic	0.0010	D;.
Polyphen		0.98	.;D
Vest4		0.92
MutPred		0.82		Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);
MVP		0.85
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.82
gMVP		0.80

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: rs121908352; hg19: chr10-73544808;