NM_022124.6:c.3074G>A

Variant names:

• chr10-71707017-G-A
• rs143179070
• NM_022124.6:c.3074G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.3074G>A​(p.Gly1025Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,607,446 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts 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 0.0033 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (6 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:10
• Conservation: PhyloP100: 9.96
• Publications: 9 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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011636496).
• BP6: Variant 10-71707017-G-A is Benign according to our data. Variant chr10-71707017-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45908.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00335 (510/152364) while in subpopulation AFR AF = 0.0111 (463/41588). AF 95% confidence interval is 0.0103. There are 4 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.3074G>A	p.Gly1025Asp	missense	Exon 26 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3074G>A	p.Gly1025Asp	missense	Exon 26 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.3074G>A	p.Gly1025Asp	missense	Exon 26 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.3074G>A	p.Gly1025Asp	missense	Exon 26 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.3074G>A	p.Gly1025Asp	missense	Exon 26 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.3074G>A	p.Gly1025Asp	missense	Exon 26 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 508 AN: 152246 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.000927 AC: 219 AN: 236206 AF XY: 0.000623

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000691

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000375

Gnomad OTH exome AF: 0.000861

GnomAD4 exome AF: 0.000403 AC: 587 AN: 1455082 Hom.: 6 Cov.: 31 AF XY: 0.000343 AC XY: 248 AN XY: 723134

African (AFR) AF: 0.0133 AC: 443 AN: 33398

American (AMR) AF: 0.000707 AC: 31 AN: 43868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.000507 AC: 20 AN: 39412

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52682

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5756

European-Non Finnish (NFE) AF: 0.0000307 AC: 34 AN: 1109086

Other (OTH) AF: 0.000815 AC: 49 AN: 60144

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152364 Hom.: 4 Cov.: 33 AF XY: 0.00336 AC XY: 250 AN XY: 74514

African (AFR) AF: 0.0111 AC: 463 AN: 41588

American (AMR) AF: 0.00216 AC: 33 AN: 15308

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

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00106 Hom.: 4

Bravo AF: 0.00344

ESP6500AA AF: 0.00971 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000975 AC: 118

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
-	-	3	not provided (3)
-	-	3	not specified (3)
-	1	2	Usher syndrome type 1D (3)
-	2	-	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	1	CDH23-related disorder (1)
-	1	-	Childhood onset hearing loss (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
REVEL	Pathogenic	0.93
Sift4G	Uncertain	0.011	D
Polyphen		0.88	P
Vest4		0.85
MVP		0.87
ClinPred		0.031	T
GERP RS		5.3
Varity_R		0.55
gMVP		0.71
Mutation Taster		=68/32	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: rs143179070; hg19: chr10-73466774;