10-71510109-A-G

Variant names:

• chr10-71510109-A-G
• rs61732490
• NM_022124.6:c.173A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022124.6(CDH23):​c.173A>G​(p.Gln58Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,613,970 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q58Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (44 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.55
• Publications: 6 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-AS1 (HGNC:31433): (CDH23 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.010118365).
• BP6: Variant 10-71510109-A-G is Benign according to our data. Variant chr10-71510109-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1975/152266) while in subpopulation AFR AF = 0.0409 (1697/41534). AF 95% confidence interval is 0.0392. There are 38 homozygotes in GnomAd4. There are 994 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR 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.173A>G	p.Gln58Arg	missense	Exon 4 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.173A>G	p.Gln58Arg	missense	Exon 4 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.173A>G	p.Gln58Arg	missense	Exon 4 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.173A>G	p.Gln58Arg	missense	Exon 4 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.173A>G	p.Gln58Arg	missense	Exon 4 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.173A>G	p.Gln58Arg	missense	Exon 4 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1966 AN: 152148 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00447 AC: 1115 AN: 249294 AF XY: 0.00370

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000991

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00218 AC: 3180 AN: 1461704 Hom.: 44 Cov.: 31 AF XY: 0.00203 AC XY: 1478 AN XY: 727134

African (AFR) AF: 0.0423 AC: 1416 AN: 33478

American (AMR) AF: 0.00342 AC: 153 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 470 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.000691 AC: 768 AN: 1111868

Other (OTH) AF: 0.00518 AC: 313 AN: 60374

GnomAD4 genome AF: 0.0130 AC: 1975 AN: 152266 Hom.: 38 Cov.: 32 AF XY: 0.0133 AC XY: 994 AN XY: 74466

African (AFR) AF: 0.0409 AC: 1697 AN: 41534

American (AMR) AF: 0.00712 AC: 109 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68020

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00711 Hom.: 34

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0357 AC: 142

ESP6500EA AF: 0.00180 AC: 15

ExAC AF: 0.00488 AC: 590

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12 (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	0.057
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.010	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.64	N
PhyloP100		2.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.12
Sift	Benign	0.44	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.41
ClinPred		0.0053	T
GERP RS		4.3
Varity_R		0.051
gMVP		0.38
Mutation Taster		=98/2	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: rs61732490; hg19: chr10-73269866; COSMIC: COSV107305515;