NM_022124.6:c.1469G>C

Variant names:

• chr10-71675131-G-C
• rs1227049
• NM_022124.6:c.1469G>C

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.1469G>C​(p.Gly490Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,613,382 control chromosomes in the GnomAD database, including 27,778 homozygotes. In-silico tool predicts 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. G490C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (2218 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25560 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 8.78
• Publications: 46 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=0.0017164052).
• BP6: Variant 10-71675131-G-C is Benign according to our data. Variant chr10-71675131-G-C is described in ClinVar as Benign. ClinVar VariationId is 45872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 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.1469G>C	p.Gly490Ala	missense	Exon 15 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.1469G>C	p.Gly490Ala	missense	Exon 15 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.1469G>C	p.Gly490Ala	missense	Exon 15 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.1469G>C	p.Gly490Ala	missense	Exon 15 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.1469G>C	p.Gly490Ala	missense	Exon 15 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.1469G>C	p.Gly490Ala	missense	Exon 15 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22325 AN: 152118 Hom.: 2215 Cov.: 32

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.200 AC: 49916 AN: 248990 AF XY: 0.206

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.303

Gnomad FIN exome AF: 0.331

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.178 AC: 260141 AN: 1461146 Hom.: 25560 Cov.: 32 AF XY: 0.182 AC XY: 132038 AN XY: 726832

African (AFR) AF: 0.0278 AC: 929 AN: 33476

American (AMR) AF: 0.165 AC: 7392 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4719 AN: 26134

East Asian (EAS) AF: 0.302 AC: 11985 AN: 39698

South Asian (SAS) AF: 0.286 AC: 24648 AN: 86228

European-Finnish (FIN) AF: 0.323 AC: 17249 AN: 53332

Middle Eastern (MID) AF: 0.161 AC: 926 AN: 5762

European-Non Finnish (NFE) AF: 0.164 AC: 181899 AN: 1111470

Other (OTH) AF: 0.172 AC: 10394 AN: 60352

GnomAD4 genome AF: 0.147 AC: 22342 AN: 152236 Hom.: 2218 Cov.: 32 AF XY: 0.158 AC XY: 11779 AN XY: 74446

African (AFR) AF: 0.0332 AC: 1379 AN: 41536

American (AMR) AF: 0.135 AC: 2060 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3472

East Asian (EAS) AF: 0.299 AC: 1549 AN: 5178

South Asian (SAS) AF: 0.297 AC: 1432 AN: 4828

European-Finnish (FIN) AF: 0.336 AC: 3559 AN: 10602

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.165 AC: 11236 AN: 68002

Other (OTH) AF: 0.142 AC: 300 AN: 2116

Alfa AF: 0.159 Hom.: 1674

Bravo AF: 0.125

TwinsUK AF: 0.174 AC: 644

ALSPAC AF: 0.169 AC: 651

ESP6500AA AF: 0.0354 AC: 149

ESP6500EA AF: 0.164 AC: 1387

ExAC AF: 0.199 AC: 24132

Asia WGS AF: 0.308 AC: 1071 AN: 3476

EpiCase AF: 0.165

EpiControl AF: 0.164

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not specified (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types (1)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.8
PrimateAI	Uncertain	0.65	T
REVEL	Uncertain	0.41
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.70
ClinPred		0.011	T
GERP RS		5.7
Varity_R		0.60
gMVP		0.79
Mutation Taster		=22/78	polymorphism (auto)

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: rs1227049; hg19: chr10-73434888; COSMIC: COSV54924856;