10-71732140-C-G

Variant names:

• chr10-71732140-C-G
• rs377222292
• NM_022124.6:c.3869C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022124.6(CDH23):​c.3869C>G​(p.Pro1290Arg) variant causes a missense change involving the alteration of a non-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. P1290L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• Publications: 1 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3869C>G	p.Pro1290Arg	missense_variant	Exon 32 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.3869C>G	p.Pro1290Arg	missense_variant	Exon 32 of 32		NP_001165401.1
C10orf105	NM_001168390.2	c.-6+5588G>C		intron_variant	Intron 1 of 1		NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3869C>G	p.Pro1290Arg	missense_variant	Exon 32 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	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;T;T
Eigen	Benign	0.066
Eigen_PC	Benign	0.063
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.24	.;.;N;.
PhyloP100		2.6
PrimateAI	Uncertain	0.54	T
REVEL	Uncertain	0.41
Sift4G	Benign	0.13	T;D;.;T
Polyphen		1.0	.;.;D;.
Vest4		0.24
MutPred		0.45		.;Loss of catalytic residue at P1290 (P = 0.0523);Loss of catalytic residue at P1290 (P = 0.0523);Loss of catalytic residue at P1290 (P = 0.0523);
MVP		0.75
ClinPred		0.94	D
GERP RS		3.9
Varity_R		0.096
gMVP		0.39
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs377222292; hg19: chr10-73491897;