10-71677578-G-C

Variant names:

• chr10-71677578-G-C
• rs199508694
• NM_022124.6:c.1637G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_022124.6(CDH23):​c.1637G>C​(p.Arg546Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.96

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 5 ACMG points.

• PM1: In a domain Cadherin 5 (size 100) in uniprot entity CAD23_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_022124.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1637G>C	p.Arg546Pro	missense_variant	Exon 16 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1637G>C	p.Arg546Pro	missense_variant	Exon 16 of 32		NP_001165401.1
CDH23	NM_001171931.2	c.1637G>C	p.Arg546Pro	missense_variant	Exon 16 of 26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1637G>C	p.Arg546Pro	missense_variant	Exon 16 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;T;T;.;T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;D;D;T;T;T
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.47	.;.;N;.;.;.
PrimateAI	Uncertain	0.76	T
REVEL	Uncertain	0.47
Sift4G	Uncertain	0.034	D;D;.;D;D;.
Polyphen		0.64	.;.;P;.;.;.
Vest4		0.94
MutPred		0.65		Loss of methylation at R546 (P = 0.0359);Loss of methylation at R546 (P = 0.0359);Loss of methylation at R546 (P = 0.0359);Loss of methylation at R546 (P = 0.0359);Loss of methylation at R546 (P = 0.0359);Loss of methylation at R546 (P = 0.0359);
MVP		0.85
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.86

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: rs199508694; hg19: chr10-73437335;