Genetic Variant CDH23:p.Ala2317Ser (chr10-71798473-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_022124.6(CDH23):c.6949G>T(p.Ala2317Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.88

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.085867554).

BP6

Variant 10-71798473-G-T is Benign according to our data. Variant chr10-71798473-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 162937.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.6949G>T	p.Ala2317Ser	missense_variant	Exon 50 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171933.1 link	c.229G>T	p.Ala77Ser	missense_variant	Exon 3 of 23		NP_001165404.1	Q9H251-7
CDH23	NM_001171934.1 link	c.229G>T	p.Ala77Ser	missense_variant	Exon 3 of 22		NP_001165405.1	Q9H251-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.6949G>T	p.Ala2317Ser	missense_variant	Exon 50 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 05, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala2317Ser in Exon 50 of CDH23: This variant is not expected to have clinical si gnificance because it is not well conserved across species with platypus and sev eral distant species (birds, reptiles, and fish) having a Ser at that position. In addition, computational analyses (biochemical amino acid properties, AlignGVG D, PolyPhen2, and SIFT) predict that the Ala2317Ser variant may not impact the p rotein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Benign

0.0024

T;T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.099

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.0067

MetaRNN

Benign

0.086

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

.;N;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

1.3

.;.;.;N

REVEL

Benign

0.090

Sift

Benign

0.71

.;.;.;T

Sift4G

Benign

1.0

T;.;T;T

Polyphen

0.0030

.;B;.;.

Vest4

0.15

MutPred

0.32

Gain of glycosylation at T2313 (P = 0.2095);Gain of glycosylation at T2313 (P = 0.2095);.;.;

MVP

0.71

MPC

0.14

ClinPred

0.21

GERP RS

4.6

Varity_R

0.25

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over