10-71793524-T-G

Variant names:

• chr10-71793524-T-G
• rs111033494
• NM_022124.6:c.6596T>G

Variant summary

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

The ENST00000224721.12(CDH23):​c.6596T>G​(p.Ile2199Ser) variant causes a missense change. 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. I2199N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH23 ENST00000224721.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.36
• Publications: 7 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000224721.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.6596T>G	p.Ile2199Ser	missense	Exon 48 of 70	NP_071407.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.6596T>G	p.Ile2199Ser	missense	Exon 48 of 70	ENSP00000224721.9
	CDH23	ENST00000642965.1		n.-113T>G		upstream_gene	N/A	ENSP00000495222.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.0069
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.4
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.10	T
Polyphen		0.33	B
Vest4		0.38
MutPred		0.51		Loss of stability (P = 0.0123)
MVP		0.74
ClinPred		0.77	D
GERP RS		5.1
Varity_R		0.25
gMVP		0.50
Mutation Taster		=71/29	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: rs111033494; hg19: chr10-73553281;