rs548188123

Positions:

• chr10-71803066-C-A
• chr10-71803066-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022124.6(CDH23):​c.7651C>A​(p.Pro2551Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,478 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.30

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.7651C>A	p.Pro2551Thr	missense_variant	54/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.931C>A	p.Pro311Thr	missense_variant	7/23		NP_001165404.1
CDH23	NM_001171934.1	c.931C>A	p.Pro311Thr	missense_variant	7/22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.7651C>A	p.Pro2551Thr	missense_variant	54/70	5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248234 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134612

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: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457478 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 724142

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: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.82	.;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	.;.;.;N
REVEL	Benign	0.26
Sift	Benign	0.23	.;.;.;T
Sift4G	Uncertain	0.0040	D;.;T;T
Polyphen		0.85	.;P;.;.
Vest4		0.61
MutPred		0.56		Gain of catalytic residue at P2551 (P = 0.1112);Gain of catalytic residue at P2551 (P = 0.1112);.;.;
MVP		0.91
MPC		0.26
ClinPred		0.71	D
GERP RS		5.0
Varity_R		0.17
gMVP		0.26

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: rs548188123; hg19: chr10-73562823;