rs149664909

Variant names:

• chr10-71777709-G-A
• rs149664909
• NM_022124.6:c.4875G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_022124.6(CDH23):​c.4875G>A​(p.Val1625Val) variant causes a synonymous change. The variant allele was found at a frequency of 0.000604 in 1,613,026 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).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (4 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 4.86
• Publications: 0 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: PanelApp Australia, 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: PanelApp Australia, 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

ENSG00000306531 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 10-71777709-G-A is Benign according to our data. Variant chr10-71777709-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178304.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00304 (462/152216) while in subpopulation AFR AF = 0.0105 (436/41520). AF 95% confidence interval is 0.00969. There are 2 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4875G>A	p.Val1625Val	synonymous	Exon 39 of 70	NP_071407.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4875G>A	p.Val1625Val	synonymous	Exon 39 of 70	ENSP00000224721.9	Q9H251-1
	ENSG00000306531	ENST00000819235.1		n.158-644C>T		intron	N/A
	ENSG00000306531	ENST00000819236.1		n.157-541C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 462 AN: 152098 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000804 AC: 198 AN: 246402 AF XY: 0.000597

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000699

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.000350 AC: 512 AN: 1460810 Hom.: 4 Cov.: 32 AF XY: 0.000334 AC XY: 243 AN XY: 726620

African (AFR) AF: 0.0112 AC: 376 AN: 33462

American (AMR) AF: 0.000852 AC: 38 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5742

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111518

Other (OTH) AF: 0.000613 AC: 37 AN: 60346

GnomAD4 genome AF: 0.00304 AC: 462 AN: 152216 Hom.: 2 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74412

African (AFR) AF: 0.0105 AC: 436 AN: 41520

American (AMR) AF: 0.00105 AC: 16 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00346

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	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
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		4.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs149664909; hg19: chr10-73537466;