rs74702249

Variant names:

• chr10-71706901-G-A
• rs74702249
• NM_022124.6:c.2958G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.2958G>A​(p.Leu986Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00294 in 1,599,258 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (55 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.88
• 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
• 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

ENSG00000300551 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 10-71706901-G-A is Benign according to our data. Variant chr10-71706901-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

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.2958G>A	p.Leu986Leu	synonymous	Exon 26 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.2958G>A	p.Leu986Leu	synonymous	Exon 26 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.2958G>A	p.Leu986Leu	synonymous	Exon 26 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.2958G>A	p.Leu986Leu	synonymous	Exon 26 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.2958G>A	p.Leu986Leu	synonymous	Exon 26 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.2958G>A	p.Leu986Leu	synonymous	Exon 26 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2455 AN: 152238 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00372 AC: 834 AN: 224112 AF XY: 0.00301

Gnomad AFR exome AF: 0.0567

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00155 AC: 2247 AN: 1446902 Hom.: 55 Cov.: 31 AF XY: 0.00133 AC XY: 956 AN XY: 718236

African (AFR) AF: 0.0543 AC: 1800 AN: 33138

American (AMR) AF: 0.00307 AC: 131 AN: 42728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 38886

South Asian (SAS) AF: 0.000156 AC: 13 AN: 83458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51864

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5738

European-Non Finnish (NFE) AF: 0.0000841 AC: 93 AN: 1105480

Other (OTH) AF: 0.00332 AC: 199 AN: 59866

GnomAD4 genome AF: 0.0162 AC: 2461 AN: 152356 Hom.: 72 Cov.: 33 AF XY: 0.0150 AC XY: 1116 AN XY: 74508

African (AFR) AF: 0.0562 AC: 2334 AN: 41564

American (AMR) AF: 0.00601 AC: 92 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68036

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00938 Hom.: 24

Bravo AF: 0.0188

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	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	-0.36
CADD	Benign	7.0
DANN	Benign	0.87
PhyloP100		5.9
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs74702249; hg19: chr10-73466658;