rs115113440

Variant names:

• chr10-71785671-G-A
• rs115113440
• NM_022124.6:c.5753G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71785671-G-A
• chr10-71785671-G-C
• chr10-71785671-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_022124.6(CDH23):​c.5753G>A​(p.Arg1918Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,608,082 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. 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. R1918W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 0.567
• Publications: 3 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 -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_022124.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0065231025).
• BP6: Variant 10-71785671-G-A is Benign according to our data. Variant chr10-71785671-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45992.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0016 (244/152312) while in subpopulation AFR AF = 0.00534 (222/41560). AF 95% confidence interval is 0.00477. There are 0 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.5753G>A	p.Arg1918Gln	missense	Exon 44 of 70	NP_071407.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.5753G>A	p.Arg1918Gln	missense	Exon 44 of 70	ENSP00000224721.9	Q9H251-1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000410 AC: 98 AN: 238958 AF XY: 0.000317

Gnomad AFR exome AF: 0.00567

Gnomad AMR exome AF: 0.000356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1455770 Hom.: 0 Cov.: 30 AF XY: 0.000169 AC XY: 122 AN XY: 723442

African (AFR) AF: 0.00609 AC: 203 AN: 33322

American (AMR) AF: 0.000317 AC: 14 AN: 44106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.0000709 AC: 6 AN: 84600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1109412

Other (OTH) AF: 0.000316 AC: 19 AN: 60172

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74478

African (AFR) AF: 0.00534 AC: 222 AN: 41560

American (AMR) AF: 0.000915 AC: 14 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.00171

ESP6500AA AF: 0.00427 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000562 AC: 68

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	CDH23-related disorder (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Cone-rod 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	0.065
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N
PhyloP100		0.57
PrimateAI	Benign	0.22	T
REVEL	Benign	0.059
Sift4G	Benign	0.21	T
Polyphen		0.073	B
Vest4		0.40
MVP		0.58
ClinPred		0.013	T
GERP RS		2.3
Varity_R		0.072
gMVP		0.36
Mutation Taster		=36/64	disease causing

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: rs115113440; hg19: chr10-73545428; COSMIC: COSV56480680;