10-71803312-G-C

Variant names:

• chr10-71803312-G-C
• rs1554876347
• NM_022124.6:c.7764G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022124.6(CDH23):​c.7764G>C​(p.Glu2588Asp) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2588Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0620
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09408069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.7764G>C	p.Glu2588Asp	missense_variant	Exon 55 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.1044G>C	p.Glu348Asp	missense_variant	Exon 8 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.1044G>C	p.Glu348Asp	missense_variant	Exon 8 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.7764G>C	p.Glu2588Asp	missense_variant	Exon 55 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.022	T;T;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.95	.;L;.;.
PhyloP100		0.062
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.45	.;.;.;N
REVEL	Benign	0.071
Sift	Benign	0.52	.;.;.;T
Sift4G	Uncertain	0.0050	D;.;T;D
Polyphen		0.0	.;B;.;.
Vest4		0.14
MutPred		0.42		Loss of glycosylation at P2590 (P = 0.1179);Loss of glycosylation at P2590 (P = 0.1179);.;.;
MVP		0.49
MPC		0.13
ClinPred		0.065	T
GERP RS		4.1
Varity_R		0.052
gMVP		0.18
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1554876347; hg19: chr10-73563069;