10-71732317-G-C

Variant names:

• chr10-71732317-G-C
• rs768452198
• NM_022124.6:c.4046G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022124.6(CDH23):​c.4046G>C​(p.Arg1349Pro) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1349C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.08
• Publications: 0 publications found

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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.4046G>C	p.Arg1349Pro	missense	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.4046G>C	p.Arg1349Pro	missense	Exon 32 of 32	NP_001165401.1
	C10orf105	NM_001168390.2		c.-6+5411C>G		intron	N/A	NP_001161862.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4046G>C	p.Arg1349Pro	missense	Exon 32 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.4046G>C	p.Arg1349Pro	missense	Exon 32 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.4043G>C	p.Arg1348Pro	missense	Exon 32 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.1
PrimateAI	Benign	0.39	T
REVEL	Benign	0.20
Sift4G	Uncertain	0.012	D
Polyphen		0.98	D
Vest4		0.59
MutPred		0.71		Loss of catalytic residue at R1349 (P = 0.0051)
MVP		0.87
ClinPred		0.96	D
GERP RS		2.1
Varity_R		0.74
gMVP		0.86
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs768452198; hg19: chr10-73492074;