NM_022124.6:c.380A>G

Variant names:

• chr10-71511163-A-G
• rs876657754
• NM_022124.6:c.380A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PM3 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.380A>G (NM_022124.6(CDH23):c.380A>G (p.Asp127Gly)) variant in CDH23 is a missense variant predicted to cause substitution of aspartate by glycine at amino acid 127. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.796 which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in one individual with autosomal recessive Usher syndrome. For this individual, they were compound heterozygous for the variant and a pathogenic variant (NM_022124.6(CDH23):c.1949dup (p.Leu651fs) (SCV000271345.2) ) and this individual was confirmed in trans by family testing (1.0 point, PM3; LMM internal data). The patient with the variant had congenital severe-profound hearing loss with vestibular complications and ophthalmology-related issues, features highly specific to Usher syndrome (LMM Internal Data; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP. In summary, this variant is classified as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_supporting, PP3, PM3, PP4 (ClinGen Hearing Loss VCEP Specifications Version 2; 6/27/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576804/MONDO:0019501/005

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.68
• Publications: 4 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-AS1 (HGNC:31433): (CDH23 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.380A>G	p.Asp127Gly	missense	Exon 6 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.380A>G	p.Asp127Gly	missense	Exon 6 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.380A>G	p.Asp127Gly	missense	Exon 6 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.380A>G	p.Asp127Gly	missense	Exon 6 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.380A>G	p.Asp127Gly	missense	Exon 6 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.380A>G	p.Asp127Gly	missense	Exon 6 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
1	-	-	Pituitary adenoma 5, multiple types (1)
1	-	-	Rare genetic deafness (1)
1	-	-	Usher syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.59		Loss of stability (P = 0.0932)
MVP		0.92
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		-0.049	Neutral
Varity_R		0.38
gMVP		0.75
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs876657754; hg19: chr10-73270920;