rs185917383

Variant names:

• chr10-71617337-C-T
• rs185917383
• NM_022124.6:c.1078C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_022124.6(CDH23):​c.1078C>T​(p.Leu360Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,613,976 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts 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. L360L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (26 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:10
• Conservation: PhyloP100: 2.44
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 10-71617337-C-T is Benign according to our data. Variant chr10-71617337-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000919 (140/152300) while in subpopulation SAS AF = 0.0133 (64/4818). AF 95% confidence interval is 0.0107. There are 3 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1078C>T	p.Leu360Leu	synonymous	Exon 11 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.1078C>T	p.Leu360Leu	synonymous	Exon 11 of 32	NP_001165401.1
	CDH23	NM_001171931.2		c.1078C>T	p.Leu360Leu	synonymous	Exon 11 of 26	NP_001165402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.1078C>T	p.Leu360Leu	synonymous	Exon 11 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.1078C>T	p.Leu360Leu	synonymous	Exon 11 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.1078C>T	p.Leu360Leu	synonymous	Exon 11 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00236 AC: 589 AN: 249330 AF XY: 0.00297

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000531

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00128 AC: 1869 AN: 1461676 Hom.: 26 Cov.: 31 AF XY: 0.00170 AC XY: 1235 AN XY: 727116

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00693 AC: 181 AN: 26136

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

South Asian (SAS) AF: 0.0140 AC: 1211 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53368

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.000279 AC: 310 AN: 1111868

Other (OTH) AF: 0.00176 AC: 106 AN: 60374

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152300 Hom.: 3 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74482

African (AFR) AF: 0.0000481 AC: 2 AN: 41562

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4818

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

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68020

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

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.000725

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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	-	CDH23-related disorder (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		2.4
PromoterAI		-0.0038	Neutral
Mutation Taster		=96/4	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: rs185917383; hg19: chr10-73377094; COSMIC: COSV54944460;