rs121908353

Positions:

• chr10-71812822-C-G
• chr10-71812822-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022124.6(CDH23):​c.9565C>G​(p.Arg3189Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R3189Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.9565C>G	p.Arg3189Gly	missense_variant	68/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.9565C>G	p.Arg3189Gly	missense_variant	68/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247794 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461110 Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 4 AN XY: 726794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.93
MutPred		0.63		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);.;.;
MVP		0.89
MPC		0.26
ClinPred		0.80	D
GERP RS		4.9
Varity_R		0.84
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908353; hg19: chr10-73572579;