rs727502928

Variant names:

• chr10-71797104-G-A
• rs727502928
• NM_022124.6:c.6713G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71797104-G-A
• chr10-71797104-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_022124.6(CDH23):​c.6713G>A​(p.Gly2238Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2238R) has been classified as Uncertain significance. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.44
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 10-71797104-G-A is Pathogenic according to our data. Variant chr10-71797104-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3601546.Status of the report is criteria_provided_single_submitter, 1 stars.

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.6713G>A	p.Gly2238Glu	missense splice_region	Exon 49 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.-8G>A		splice_region	Exon 2 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.-8G>A		splice_region	Exon 2 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.6713G>A	p.Gly2238Glu	missense splice_region	Exon 49 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.249G>A		non_coding_transcript_exon	Exon 1 of 21
	CDH23	ENST00000642965.1		n.*556G>A		splice_region non_coding_transcript_exon	Exon 4 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454936 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723950

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106632

Other (OTH) AF: 0.00 AC: 0 AN: 60140

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive nonsyndromic hearing loss 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.050	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.4
PrimateAI	Uncertain	0.72	T
REVEL	Pathogenic	0.73
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Gain of ubiquitination at K2243 (P = 0.0688)
MVP		0.82
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.83
gMVP		0.87
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
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: rs727502928; hg19: chr10-73556861;