rs2305207

Variant names:

• chr10-71645960-G-A
• rs2305207
• NM_022124.6:c.1270G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_022124.6(CDH23):​c.1270G>A​(p.Val424Met) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,612,916 control chromosomes in the GnomAD database, including 1 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 0.000072 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.53
• 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 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

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032257378).
• BP6: Variant 10-71645960-G-A is Benign according to our data. Variant chr10-71645960-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1006937.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000722 (11/152350) while in subpopulation SAS AF = 0.00186 (9/4832). AF 95% confidence interval is 0.000971. There are 1 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1270G>A	p.Val424Met	missense	Exon 13 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.1270G>A	p.Val424Met	missense	Exon 13 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.1270G>A	p.Val424Met	missense	Exon 13 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.1270G>A	p.Val424Met	missense	Exon 13 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.1270G>A	p.Val424Met	missense	Exon 13 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.1270G>A	p.Val424Met	missense	Exon 13 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000198 AC: 49 AN: 247700 AF XY: 0.000283

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000391

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1460566 Hom.: 0 Cov.: 32 AF XY: 0.000151 AC XY: 110 AN XY: 726570

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.0000225 AC: 1 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39686

South Asian (SAS) AF: 0.00144 AC: 124 AN: 86082

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111514

Other (OTH) AF: 0.0000332 AC: 2 AN: 60304

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000152 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000190 AC: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.16
Sift	Benign	0.094	T
Sift4G	Uncertain	0.018	D
Polyphen		0.97	D
Vest4		0.36
MutPred		0.47		Gain of phosphorylation at Y421 (P = 0.18)
MVP		0.79
ClinPred		0.13	T
GERP RS		4.0
Varity_R		0.041
gMVP		0.26
Mutation Taster		=79/21	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: rs2305207; hg19: chr10-73405717;