rs397517312

Variant names:

• chr10-71682452-C-A
• rs397517312
• NM_022124.6:c.1866C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71682452-C-A
• chr10-71682452-C-T

Variant summary

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

The NM_022124.6(CDH23):​c.1866C>A​(p.Ser622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,326 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S622S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• 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.1866C>A	p.Ser622Arg	missense_variant	Exon 18 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1866C>A	p.Ser622Arg	missense_variant	Exon 18 of 32		NP_001165401.1
CDH23	NM_001171931.2	c.1866C>A	p.Ser622Arg	missense_variant	Exon 18 of 26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1866C>A	p.Ser622Arg	missense_variant	Exon 18 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459326 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725698

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 85588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110868

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	6.3
DANN	Benign	0.97
DEOGEN2	Benign	0.027	T;T;T;.;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.045	.;.;N;.;.;.
PhyloP100		-1.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	.;.;.;.;.;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.019	.;.;.;.;.;D
Sift4G	Uncertain	0.057	T;T;.;T;D;.
Polyphen		0.94	.;.;P;.;.;.
Vest4		0.86
MutPred		0.60		Gain of phosphorylation at S624 (P = 0.1527);Gain of phosphorylation at S624 (P = 0.1527);Gain of phosphorylation at S624 (P = 0.1527);Gain of phosphorylation at S624 (P = 0.1527);Gain of phosphorylation at S624 (P = 0.1527);Gain of phosphorylation at S624 (P = 0.1527);
MVP		0.64
ClinPred		0.89	D
GERP RS		-2.3
Varity_R		0.62
gMVP		0.69
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397517312; hg19: chr10-73442209;