10-71566886-G-A

Variant names:

• chr10-71566886-G-A
• rs199514829
• NM_022124.6:c.574G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_022124.6(CDH23):​c.574G>A​(p.Glu192Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. E192Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27859482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.574G>A	p.Glu192Lys	missense_variant	Exon 7 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.574G>A	p.Glu192Lys	missense_variant	Exon 7 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249006 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135120

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: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461588 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727086

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: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T;T;.;.;.;T;.;.
Eigen	Benign	-0.040
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.14	.;.;N;N;.;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.82	N;.;.;.;.;.;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.18	T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.28	T;T;.;T;T;T;T;.;.
Polyphen		0.45, 0.27	.;.;B;B;.;.;.;.;.
Vest4		0.56
MutPred		0.68		Gain of ubiquitination at E192 (P = 0.0351);Gain of ubiquitination at E192 (P = 0.0351);Gain of ubiquitination at E192 (P = 0.0351);Gain of ubiquitination at E192 (P = 0.0351);Gain of ubiquitination at E192 (P = 0.0351);.;Gain of ubiquitination at E192 (P = 0.0351);Gain of ubiquitination at E192 (P = 0.0351);.;
MVP		0.49
ClinPred		0.18	T
GERP RS		5.7
Varity_R		0.20
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199514829; hg19: chr10-73326643;