rs397517310

Variant names:

• chr10-71677606-C-T
• rs397517310
• NM_022124.6:c.1665C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_022124.6(CDH23):​c.1665C>T​(p.Asn555Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,604,272 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -1.83
• 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
• 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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-71677606-C-T is Benign according to our data. Variant chr10-71677606-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45880.
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.

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.1665C>T	p.Asn555Asn	synonymous	Exon 16 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.1665C>T	p.Asn555Asn	synonymous	Exon 16 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.1665C>T	p.Asn555Asn	synonymous	Exon 16 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.1665C>T	p.Asn555Asn	synonymous	Exon 16 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.1665C>T	p.Asn555Asn	synonymous	Exon 16 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.1665C>T	p.Asn555Asn	synonymous	Exon 16 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000432 AC: 10 AN: 231512 AF XY: 0.0000639

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000382

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000248 AC: 36 AN: 1452108 Hom.: 0 Cov.: 31 AF XY: 0.0000250 AC XY: 18 AN XY: 721118

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.0000460 AC: 2 AN: 43446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25858

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39350

South Asian (SAS) AF: 0.0000477 AC: 4 AN: 83904

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52648

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5760

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1107756

Other (OTH) AF: 0.00 AC: 0 AN: 60062

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74340

African (AFR) AF: 0.0000483 AC: 2 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000830 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	1	-	CDH23-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (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	-0.62
CADD	Benign	0.99
DANN	Benign	0.73
PhyloP100		-1.8
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517310; hg19: chr10-73437363;