rs121908347

Positions:

• chr10-71739772-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_022124.6(CDH23):​c.4488G>C​(p.Gln1496His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,455,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.70

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-71739772-G-C is Pathogenic according to our data. Variant chr10-71739772-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71739772-G-C is described in Lovd as [Pathogenic]. Variant chr10-71739772-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.4488G>C	p.Gln1496His	missense_variant, splice_region_variant	36/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.4488G>C	p.Gln1496His	missense_variant, splice_region_variant	36/70	5	NM_022124.6	ENSP00000224721	P1
CDH23	ENST00000398792.3	n.1177G>C		splice_region_variant, non_coding_transcript_exon_variant	7/9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455984 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	Published functional studies demonstrate a damaging effect by a cryptic intronic splice site 103bp downstream, which indicates a truncation and loss of function of CDH23 (Bolz et al., 2001); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31706454, 31231422, 12075507, 11138009, 18273900, 18429043, 27599893, 29986705) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 28, 2023	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1496 of the CDH23 protein (p.Gln1496His). This variant also falls at the last nucleotide of exon 36, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Usher syndrome (PMID: 11138009, 30459346, 31231422). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4915). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11138009). For these reasons, this variant has been classified as Pathogenic. -

Pituitary adenoma 5, multiple types Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Usher syndrome type 1D Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

Usher syndrome type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	0.057
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.60	.;N
MutationTaster	Benign	0.97	A;A
PrimateAI	Uncertain	0.61	T
REVEL	Uncertain	0.31
Sift4G	Uncertain	0.014	D;.
Polyphen		0.28	.;B
Vest4		0.28
MutPred		0.47		Gain of glycosylation at S1500 (P = 0.14);Gain of glycosylation at S1500 (P = 0.14);
MVP		0.93
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908347; hg19: chr10-73499529;