rs397517365

Positions:

• chr10-71811323-A-C

Variant summary

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

The NM_022124.6(CDH23):​c.9086A>C​(p.Gln3029Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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]

CDH23 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.9086A>C	p.Gln3029Pro	missense_variant	63/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.2366A>C	p.Gln789Pro	missense_variant	16/23		NP_001165404.1
CDH23	NM_001171934.1	c.2366A>C	p.Gln789Pro	missense_variant	16/22		NP_001165405.1
LOC124902446	XR_007062185.1	n.1267+169T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.9086A>C	p.Gln3029Pro	missense_variant	63/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

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

Oct 07, 2011

Variant classified as Uncertain Significance - Favor Benign. The Gln3029Pro vari ant in CDH23 has not been reported in the literature nor previously identified b y our laboratory. Computational analyses (biochemical amino acid properties, hom ology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. In the absence of additional information, such as identification of a second CDH23 variant in this individual, control data, segregation studies or functional analysis, the clinical significance of this variant cannot be dete rmined at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	.;L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.3	.;.;.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	.;.;.;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.83	.;P;.;.
Vest4		0.92
MutPred		0.56		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;
MVP		0.78
MPC		0.42
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.49
gMVP		0.87

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: rs397517365; hg19: chr10-73571080;