rs1554857840

chr10-71702034-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_022124.6(CDH23):c.2410G>A(p.Asp804Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D804D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.96

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 10-71702034-G-A is Pathogenic according to our data. Variant chr10-71702034-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522662.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.2410G>A	p.Asp804Asn	missense_variant	23/70	ENST00000224721.12
CDH23	NM_001171930.2	c.2410G>A	p.Asp804Asn	missense_variant	23/32
CDH23	NM_001171931.2	c.2410G>A	p.Asp804Asn	missense_variant	23/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.2410G>A	p.Asp804Asn	missense_variant	23/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Usher syndrome type 1D Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;D;.;T;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
Sift4G	Pathogenic	0.0	D;D;.;D;D;.
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.99
MutPred		0.89		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.89
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554857840; hg19: chr10-73461791;