rs876657636

chr10-71702662-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.2701G>A(p.Glu901Lys) 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.87

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, 0.979
• PP5: Variant 10-71702662-G-A is Pathogenic according to our data. Variant chr10-71702662-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228248.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.2701G>A	p.Glu901Lys	missense_variant	24/70	ENST00000224721.12
CDH23	NM_001171930.2	c.2701G>A	p.Glu901Lys	missense_variant	24/32
CDH23	NM_001171931.2	c.2701G>A	p.Glu901Lys	missense_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.2701G>A	p.Glu901Lys	missense_variant	24/70	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

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 05, 2015

The p.Glu901Lys variant in CDH23 has not been previously reported in individuals with hearing loss or Usher syndrome and was absent from large population studie s. Computational prediction tools and conservation analyses suggest that the p.G lu901Lys variant may impact the protein. This variant is found to be likely in t rans with a pathogenic variant in an individual with hearing loss, which increas es the likelihood that the p.Glu901Lys variant is pathogenic. In summary, althou gh additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;T;D;.;T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Pathogenic	0.0	D;D;.;D;D;.
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.94
MutPred		0.86		Gain of methylation at E901 (P = 0.0116);Gain of methylation at E901 (P = 0.0116);Gain of methylation at E901 (P = 0.0116);Gain of methylation at E901 (P = 0.0116);Gain of methylation at E901 (P = 0.0116);Gain of methylation at E901 (P = 0.0116);
MVP		0.84
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.32
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657636; hg19: chr10-73462419;