rs866435331

Positions:

• chr10-71712685-C-G
• chr10-71712685-C-T

Variant summary

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

The NM_022124.6(CDH23):​c.3241C>G​(p.Arg1081Gly) 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. R1081Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.477

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

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	UniProt
CDH23	NM_022124.6	c.3241C>G	p.Arg1081Gly	missense_variant	28/70	ENST00000224721.12
C10orf105	NM_001164375.3	c.*3251G>C		3_prime_UTR_variant	2/2	ENST00000441508.4
CDH23	NM_001171930.2	c.3241C>G	p.Arg1081Gly	missense_variant	28/32
C10orf105	NM_001168390.2	c.*3251G>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3241C>G	p.Arg1081Gly	missense_variant	28/70	5	NM_022124.6	P1
C10orf105	ENST00000441508.4	c.*3251G>C		3_prime_UTR_variant	2/2	1	NM_001164375.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;T;T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.16	.;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
REVEL	Benign	0.27
Sift4G	Uncertain	0.0040	D;D;.;D;.
Polyphen		0.19	.;.;B;.;.
Vest4		0.80
MutPred		0.58		Loss of methylation at K1080 (P = 0.0585);Loss of methylation at K1080 (P = 0.0585);Loss of methylation at K1080 (P = 0.0585);Loss of methylation at K1080 (P = 0.0585);Loss of methylation at K1080 (P = 0.0585);
MVP		0.77
ClinPred		0.91	D
GERP RS		3.0
Varity_R		0.40
gMVP		0.65

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: rs866435331; hg19: chr10-73472442;