rs56013867

Variant names:

• chr10-71798376-G-C
• rs56013867
• NM_022124.6:c.6852G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-71798376-G-C
• chr10-71798376-G-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.6852G>C​(p.Leu2284Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00571 in 1,613,818 control chromosomes in the GnomAD database, including 28 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 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (25 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 5.03
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-71798376-G-C is Benign according to our data. Variant chr10-71798376-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46020.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00471 (718/152308) while in subpopulation AMR AF = 0.00882 (135/15306). AF 95% confidence interval is 0.00761. There are 3 homozygotes in GnomAd4. There are 376 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown 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.6852G>C	p.Leu2284Leu	synonymous	Exon 50 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.132G>C	p.Leu44Leu	synonymous	Exon 3 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.132G>C	p.Leu44Leu	synonymous	Exon 3 of 22	NP_001165405.1	Q9H251-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.6852G>C	p.Leu2284Leu	synonymous	Exon 50 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.388G>C		non_coding_transcript_exon	Exon 2 of 21
	CDH23	ENST00000642965.1		n.*695G>C		non_coding_transcript_exon	Exon 5 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 718 AN: 152190 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00619

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00454 AC: 1132 AN: 249254 AF XY: 0.00450

Gnomad AFR exome AF: 0.000903

Gnomad AMR exome AF: 0.00597

Gnomad ASJ exome AF: 0.00636

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00622

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.00744

GnomAD4 exome AF: 0.00581 AC: 8495 AN: 1461510 Hom.: 25 Cov.: 32 AF XY: 0.00574 AC XY: 4175 AN XY: 727052

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.00626 AC: 280 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 158 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86250

European-Finnish (FIN) AF: 0.00639 AC: 341 AN: 53402

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00653 AC: 7256 AN: 1111696

Other (OTH) AF: 0.00603 AC: 364 AN: 60368

GnomAD4 genome AF: 0.00471 AC: 718 AN: 152308 Hom.: 3 Cov.: 32 AF XY: 0.00505 AC XY: 376 AN XY: 74484

African (AFR) AF: 0.00144 AC: 60 AN: 41554

American (AMR) AF: 0.00882 AC: 135 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00619 AC: 421 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00578 Hom.: 3

Bravo AF: 0.00434

EpiCase AF: 0.00507

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	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	-0.54
CADD	Benign	1.3
DANN	Benign	0.57
PhyloP100		5.0
Mutation Taster		=63/37	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: rs56013867; hg19: chr10-73558133;