10-71732140-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022124.6(CDH23):​c.3869C>A​(p.Pro1290Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign 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. P1290L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34526378).

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.3869C>A	p.Pro1290Gln	missense	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3869C>A	p.Pro1290Gln	missense	Exon 32 of 32	NP_001165401.1
	C10orf105	NM_001168390.2		c.-6+5588G>T		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.3869C>A	p.Pro1290Gln	missense	Exon 32 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.3869C>A	p.Pro1290Gln	missense	Exon 32 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.3866C>A	p.Pro1289Gln	missense	Exon 32 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.72	N
PhyloP100		2.6
PrimateAI	Benign	0.48	T
REVEL	Benign	0.17
Sift4G	Uncertain	0.023	D
Polyphen		0.88	P
Vest4		0.52
MutPred		0.36		Loss of catalytic residue at P1290 (P = 0.0354)
MVP		0.75
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.10
gMVP		0.38
Mutation Taster		=72/28	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;