10-71732010-C-T

Variant names:

• chr10-71732010-C-T
• rs202204597
• NM_022124.6:c.3739C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_022124.6(CDH23):​c.3739C>T​(p.Arg1247Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1247H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 0.400
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19566825).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.3739C>T	p.Arg1247Cys	missense	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3739C>T	p.Arg1247Cys	missense	Exon 32 of 32	NP_001165401.1
	C10orf105	NM_001168390.2		c.-6+5718G>A		intron	N/A	NP_001161862.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3739C>T	p.Arg1247Cys	missense	Exon 32 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.3739C>T	p.Arg1247Cys	missense	Exon 32 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.3736C>T	p.Arg1246Cys	missense	Exon 32 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000229 AC: 57 AN: 248914 AF XY: 0.000252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000452

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000334 AC: 488 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.000331 AC XY: 241 AN XY: 727040

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000134 AC: 6 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53388

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

European-Non Finnish (NFE) AF: 0.000418 AC: 465 AN: 1111792

Other (OTH) AF: 0.000199 AC: 12 AN: 60362

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74338

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types (1)
-	1	-	CDH23-related disorder (1)
-	1	-	not specified (1)
-	1	-	Retinal dystrophy (1)
-	1	-	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.042
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.40
PrimateAI	Benign	0.32	T
REVEL	Uncertain	0.51
Sift4G	Uncertain	0.018	D
Polyphen		0.92	P
Vest4		0.12
MVP		0.80
ClinPred		0.27	T
GERP RS		3.9
Varity_R		0.13
gMVP		0.32
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: rs202204597; hg19: chr10-73491767; COSMIC: COSV106385382;