10-71803371-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_022124.6(CDH23):c.7823G>C(p.Arg2608Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R2608H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.78

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_022124.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.7823G>C	p.Arg2608Pro	missense_variant	55/70	ENST00000224721.12
CDH23	NM_001171933.1	c.1103G>C	p.Arg368Pro	missense_variant	8/23
CDH23	NM_001171934.1	c.1103G>C	p.Arg368Pro	missense_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.7823G>C	p.Arg2608Pro	missense_variant	55/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0024	T;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.0060	D;.;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.72
MutPred		0.70		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;
MVP		0.72
MPC		0.22
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.58
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-73563128;