NM_022124.6:c.2878G>A

Variant names:

• chr10-71705055-G-A
• rs111033458
• NM_022124.6:c.2878G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.2878G>A​(p.Glu960Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,612,632 control chromosomes in the GnomAD database, including 19 homozygotes. 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). The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 2.73
• 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

ENSG00000300551 (HGNC:):

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_022124.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.010432005).
• BP6: Variant 10-71705055-G-A is Benign according to our data. Variant chr10-71705055-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45904.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00293 (446/152304) while in subpopulation NFE AF = 0.00468 (318/68010). AF 95% confidence interval is 0.00425. There are 2 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown 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.2878G>A	p.Glu960Lys	missense	Exon 25 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.2878G>A	p.Glu960Lys	missense	Exon 25 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.2878G>A	p.Glu960Lys	missense	Exon 25 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.2878G>A	p.Glu960Lys	missense	Exon 25 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.2878G>A	p.Glu960Lys	missense	Exon 25 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.2878G>A	p.Glu960Lys	missense	Exon 25 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00302 AC: 742 AN: 245864 AF XY: 0.00306

Gnomad AFR exome AF: 0.000597

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00499

Gnomad OTH exome AF: 0.00350

GnomAD4 exome AF: 0.00376 AC: 5490 AN: 1460328 Hom.: 17 Cov.: 32 AF XY: 0.00373 AC XY: 2711 AN XY: 726500

African (AFR) AF: 0.000568 AC: 19 AN: 33474

American (AMR) AF: 0.00349 AC: 156 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

European-Finnish (FIN) AF: 0.00161 AC: 84 AN: 52156

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00454 AC: 5044 AN: 1111826

Other (OTH) AF: 0.00293 AC: 177 AN: 60356

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74480

African (AFR) AF: 0.000866 AC: 36 AN: 41570

American (AMR) AF: 0.00438 AC: 67 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00468 AC: 318 AN: 68010

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00402 Hom.: 3

Bravo AF: 0.00315

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000964 AC: 4

ESP6500EA AF: 0.00418 AC: 35

ExAC AF: 0.00314 AC: 380

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00510

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	CDH23-related disorder (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	0.098
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.7
PrimateAI	Benign	0.38	T
REVEL	Benign	0.091
Sift4G	Benign	0.60	T
Polyphen		0.0040	B
Vest4		0.43
MVP		0.72
ClinPred		0.014	T
GERP RS		4.6
Varity_R		0.066
gMVP		0.39
Mutation Taster		=90/10	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: rs111033458; hg19: chr10-73464812; COSMIC: COSV54934710;