10-71798573-C-G

Variant names:

• chr10-71798573-C-G
• rs371522435
• NM_022124.6:c.7049C>G

Variant summary

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

The NM_022124.6(CDH23):​c.7049C>G​(p.Ser2350Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2350L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.41
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.7049C>G	p.Ser2350Trp	missense_variant	Exon 50 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.329C>G	p.Ser110Trp	missense_variant	Exon 3 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.329C>G	p.Ser110Trp	missense_variant	Exon 3 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.7049C>G	p.Ser2350Trp	missense_variant	Exon 50 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	.;M;.;.
PhyloP100		3.4
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.0	.;.;.;D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Uncertain	0.0050	D;.;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.66
MutPred		0.31		Loss of disorder (P = 0.0016);Loss of disorder (P = 0.0016);.;.;
MVP		0.78
MPC		0.70
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.59
gMVP		0.57
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: -24

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

Other links and lift over

dbSNP: rs371522435; hg19: chr10-73558330;