rs146819206

Variant names:

• chr10-71798442-G-A
• rs146819206
• NM_022124.6:c.6918G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.6918G>A​(p.Leu2306Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,613,968 control chromosomes in the GnomAD database, including 40 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. L2306L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (40 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 3.23
• Publications: 3 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, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-71798442-G-A is Benign according to our data. Variant chr10-71798442-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46022.
• BP7: Synonymous conserved (PhyloP=3.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00115 (175/152322) while in subpopulation SAS AF = 0.0159 (77/4832). AF 95% confidence interval is 0.0131. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 40 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.6918G>A	p.Leu2306Leu	synonymous	Exon 50 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.198G>A	p.Leu66Leu	synonymous	Exon 3 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.198G>A	p.Leu66Leu	synonymous	Exon 3 of 22	NP_001165405.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.6918G>A	p.Leu2306Leu	synonymous	Exon 50 of 70	ENSP00000224721.9
	CDH23	ENST00000475158.1	TSL:1	n.454G>A		non_coding_transcript_exon	Exon 2 of 21
	CDH23	ENST00000642965.1		n.*761G>A		non_coding_transcript_exon	Exon 5 of 25	ENSP00000495222.1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00317 AC: 791 AN: 249188 AF XY: 0.00402

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000956

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00188 AC: 2749 AN: 1461646 Hom.: 40 Cov.: 32 AF XY: 0.00242 AC XY: 1757 AN XY: 727114

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000805 AC: 36 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00677 AC: 177 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0188 AC: 1623 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53394

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5766

European-Non Finnish (NFE) AF: 0.000623 AC: 693 AN: 1111826

Other (OTH) AF: 0.00268 AC: 162 AN: 60370

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74484

African (AFR) AF: 0.000120 AC: 5 AN: 41582

American (AMR) AF: 0.000784 AC: 12 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0159 AC: 77 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.000880

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Usher syndrome type 1D (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.5
DANN	Benign	0.73
PhyloP100		3.2
Mutation Taster		=97/3	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: rs146819206; hg19: chr10-73558199;