rs397517348

Variant names:

• chr10-71566930-C-A
• rs397517348
• NM_022124.6:c.618C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71566930-C-A
• chr10-71566930-C-T

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.618C>A​(p.Asn206Lys) 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 1,459,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. N206T) 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: -0.492
• Publications: 3 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=0.2592619).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. 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.618C>A	p.Asn206Lys	missense	Exon 7 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.618C>A	p.Asn206Lys	missense	Exon 7 of 32	NP_001165401.1
	CDH23	NM_001171931.2		c.618C>A	p.Asn206Lys	missense	Exon 7 of 26	NP_001165402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.618C>A	p.Asn206Lys	missense	Exon 7 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.618C>A	p.Asn206Lys	missense	Exon 7 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.618C>A	p.Asn206Lys	missense	Exon 7 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246742 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459708 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726186

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111688

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.89	N
PhyloP100		-0.49
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Benign	0.96	T
Sift4G	Uncertain	0.059	T
Polyphen		0.58	P
Vest4		0.86
MutPred		0.52		Gain of ubiquitination at N206 (P = 0.0198)
MVP		0.50
ClinPred		0.91	D
GERP RS		-2.7
Varity_R		0.41
gMVP		0.47
Mutation Taster		=40/60	disease causing

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: rs397517348; hg19: chr10-73326687;