rs746121407

Positions:

• chr10-71807995-G-A
• chr10-71807995-G-C
• chr10-71807995-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022124.6(CDH23):​c.8710G>A​(p.Val2904Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2904F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15456036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.8710G>A	p.Val2904Ile	missense_variant	60/70	ENST00000224721.12
CDH23	NM_001171933.1	c.1990G>A	p.Val664Ile	missense_variant	13/23
CDH23	NM_001171934.1	c.1990G>A	p.Val664Ile	missense_variant	13/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.8710G>A	p.Val2904Ile	missense_variant	60/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 13, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Val2904Ile va riant in CDH23 has not been previously reported in individuals with hearing loss or in large population studies. Valine (Val) at position 2904 is not conserved in evolutionary distant species and >20 species carry an isoleucine (Ile) at thi s position, raising the possibility that this change may be tolerated. In additi on, computational prediction tools suggest that the p.Val2904Ile variant may not impact the protein. In summary, while the clinical significance of the p.Val290 4Ile variant is uncertain, its lack of conservation suggests that it is more lik ely to be benign. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.0051	T;T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	.;N;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.29	.;N;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.018	.;D;.;T
Sift4G	Benign	1.0	T;.;T;T
Polyphen		0.014	.;B;.;.
Vest4		0.088
MutPred		0.47		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;.;
MVP		0.76
MPC		0.12
ClinPred		0.39	T
GERP RS		5.3
Varity_R		0.032
gMVP		0.14

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: rs746121407; hg19: chr10-73567752;