rs41281318

Variant names:

• chr10-71732316-C-T
• rs41281318
• NM_022124.6:c.4045C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.4045C>T​(p.Arg1349Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,603,690 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1349H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (20 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 4.88
• Publications: 12 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012268841).
• BP6: Variant 10-71732316-C-T is Benign according to our data. Variant chr10-71732316-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45936.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (429/152306) while in subpopulation NFE AF = 0.00473 (322/68020). AF 95% confidence interval is 0.00431. There are 1 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

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.4045C>T	p.Arg1349Cys	missense	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.4045C>T	p.Arg1349Cys	missense	Exon 32 of 32	NP_001165401.1	A0A087WYR8
	C10orf105	NM_001168390.2		c.-6+5412G>A		intron	N/A	NP_001161862.1	Q8TEF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4045C>T	p.Arg1349Cys	missense	Exon 32 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.4045C>T	p.Arg1349Cys	missense	Exon 32 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.4042C>T	p.Arg1348Cys	missense	Exon 32 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00256 AC: 588 AN: 229926 AF XY: 0.00263

Gnomad AFR exome AF: 0.000880

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000196

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00457 AC: 6637 AN: 1451384 Hom.: 20 Cov.: 31 AF XY: 0.00438 AC XY: 3159 AN XY: 721108

African (AFR) AF: 0.000782 AC: 26 AN: 33234

American (AMR) AF: 0.00265 AC: 114 AN: 43000

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39152

South Asian (SAS) AF: 0.00201 AC: 170 AN: 84740

European-Finnish (FIN) AF: 0.000247 AC: 13 AN: 52674

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.00548 AC: 6062 AN: 1106854

Other (OTH) AF: 0.00413 AC: 248 AN: 60020

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74470

African (AFR) AF: 0.00101 AC: 42 AN: 41564

American (AMR) AF: 0.00340 AC: 52 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00473 AC: 322 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00342 Hom.: 3

Bravo AF: 0.00291

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000962 AC: 4

ESP6500EA AF: 0.00475 AC: 40

ExAC AF: 0.00235 AC: 284

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	CDH23-related disorder (1)
-	1	-	Intellectual disability (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	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.053	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.9
PrimateAI	Benign	0.43	T
REVEL	Benign	0.13
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.87
ClinPred		0.025	T
GERP RS		4.0
Varity_R		0.27
gMVP		0.58
Mutation Taster		=94/6	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: rs41281318; hg19: chr10-73492073;