rs7902757

Variant names:

• chr10-71439838-C-T
• rs7902757
• NM_022124.6:c.7C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-71439838-C-T
• chr10-71439838-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.7C>T​(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 1,563,838 control chromosomes in the GnomAD database, including 5,378 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (2655 hom., cov: 33)
  • Exomes 𝑓: 0.032 (2723 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.134
• Publications: 11 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]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00406006).
• BP6: Variant 10-71439838-C-T is Benign according to our data. Variant chr10-71439838-C-T is described in ClinVar as Benign. ClinVar VariationId is 46042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

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.7C>T	p.Arg3Cys	missense	Exon 2 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.7C>T	p.Arg3Cys	missense	Exon 2 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.7C>T	p.Arg3Cys	missense	Exon 2 of 26	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.7C>T	p.Arg3Cys	missense	Exon 2 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.7C>T	p.Arg3Cys	missense	Exon 2 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.7C>T	p.Arg3Cys	missense	Exon 2 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17618 AN: 151998 Hom.: 2644 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0945

GnomAD2 exomes AF: 0.0455 AC: 8039 AN: 176796 AF XY: 0.0417

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.0306

Gnomad ASJ exome AF: 0.0356

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.0210

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0427

GnomAD4 exome AF: 0.0321 AC: 45367 AN: 1411720 Hom.: 2723 Cov.: 31 AF XY: 0.0317 AC XY: 22140 AN XY: 697690

African (AFR) AF: 0.353 AC: 11293 AN: 31994

American (AMR) AF: 0.0336 AC: 1267 AN: 37672

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 896 AN: 25316

East Asian (EAS) AF: 0.000269 AC: 10 AN: 37222

South Asian (SAS) AF: 0.0490 AC: 3923 AN: 80098

European-Finnish (FIN) AF: 0.0230 AC: 1158 AN: 50354

Middle Eastern (MID) AF: 0.0851 AC: 485 AN: 5698

European-Non Finnish (NFE) AF: 0.0217 AC: 23561 AN: 1084912

Other (OTH) AF: 0.0475 AC: 2774 AN: 58454

GnomAD4 genome AF: 0.116 AC: 17676 AN: 152118 Hom.: 2655 Cov.: 33 AF XY: 0.113 AC XY: 8383 AN XY: 74376

African (AFR) AF: 0.346 AC: 14336 AN: 41422

American (AMR) AF: 0.0567 AC: 867 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5176

South Asian (SAS) AF: 0.0543 AC: 262 AN: 4828

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10606

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1634 AN: 68004

Other (OTH) AF: 0.0935 AC: 197 AN: 2106

Alfa AF: 0.0563 Hom.: 2060

Bravo AF: 0.128

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.326 AC: 1330

ESP6500EA AF: 0.0242 AC: 202

ExAC AF: 0.0389 AC: 4607

Asia WGS AF: 0.0470 AC: 165 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not specified (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.13
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.077
Sift	Benign	0.068	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.061
ClinPred		0.013	T
GERP RS		0.54
PromoterAI		-0.24	Neutral
Varity_R		0.089
gMVP		0.46
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7902757; hg19: chr10-73199595; COSMIC: COSV54932823;