rs111033369

Variant names:

• chr10-71646475-G-A
• rs111033369
• NM_022124.6:c.1307G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71646475-G-A
• chr10-71646475-G-C
• chr10-71646475-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.1307G>A​(p.Ser436Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00324 in 1,613,778 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S436S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (6 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 7.06
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007903039).
• BP6: Variant 10-71646475-G-A is Benign according to our data. Variant chr10-71646475-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45866.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00237 (360/152178) while in subpopulation NFE AF = 0.00416 (283/67992). AF 95% confidence interval is 0.00376. There are 0 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1307G>A	p.Ser436Asn	missense	Exon 14 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.1307G>A	p.Ser436Asn	missense	Exon 14 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.1307G>A	p.Ser436Asn	missense	Exon 14 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.1307G>A	p.Ser436Asn	missense	Exon 14 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.1307G>A	p.Ser436Asn	missense	Exon 14 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.1307G>A	p.Ser436Asn	missense	Exon 14 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152060 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00276 AC: 688 AN: 249072 AF XY: 0.00286

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00519

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.00333 AC: 4874 AN: 1461600 Hom.: 6 Cov.: 31 AF XY: 0.00323 AC XY: 2346 AN XY: 727066

African (AFR) AF: 0.000627 AC: 21 AN: 33476

American (AMR) AF: 0.000738 AC: 33 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26132

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

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86252

European-Finnish (FIN) AF: 0.00189 AC: 101 AN: 53402

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5704

European-Non Finnish (NFE) AF: 0.00406 AC: 4512 AN: 1111844

Other (OTH) AF: 0.00240 AC: 145 AN: 60368

GnomAD4 genome AF: 0.00237 AC: 360 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.00219 AC XY: 163 AN XY: 74422

African (AFR) AF: 0.000386 AC: 16 AN: 41498

American (AMR) AF: 0.000980 AC: 15 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00416 AC: 283 AN: 67992

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00360 Hom.: 5

Bravo AF: 0.00222

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000730 AC: 3

ESP6500EA AF: 0.00404 AC: 34

ExAC AF: 0.00354 AC: 428

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00356

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	1	Usher syndrome type 1D (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	CDH23-related disorder (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	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.48	N
PhyloP100		7.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Uncertain	0.035	D
Polyphen		0.99	D
Vest4		0.67
MVP		0.88
ClinPred		0.020	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.53
Mutation Taster		=75/25	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: rs111033369; hg19: chr10-73406232; COSMIC: COSV54922955;