Genetic Variant CDH23:p.Ala1109Val (chr10-71712770-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_022124.6(CDH23):c.3326C>T(p.Ala1109Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A1109A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.09

Publications

1 publications found

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:

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

C10orf105 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH23	NM_022124.6	MANE Select	c.3326C>T	p.Ala1109Val	missense	Exon 28 of 70	NP_071407.4
C10orf105	NM_001164375.3	MANE Select	c.*3166G>A		3_prime_UTR	Exon 2 of 2	NP_001157847.1	Q8TEF2
CDH23	NM_001171930.2		c.3326C>T	p.Ala1109Val	missense	Exon 28 of 32	NP_001165401.1	A0A087WYR8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3326C>T	p.Ala1109Val	missense	Exon 28 of 70	ENSP00000224721.9	Q9H251-1
C10orf105	ENST00000441508.4	TSL:1 MANE Select	c.*3166G>A		3_prime_UTR	Exon 2 of 2	ENSP00000403151.2	Q8TEF2
CDH23	ENST00000616684.4	TSL:5	c.3326C>T	p.Ala1109Val	missense	Exon 28 of 32	ENSP00000482036.2	A0A087WYR8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0022

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.092

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0048

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.28

PhyloP100

4.1

PrimateAI

Benign

0.42

REVEL

Benign

0.084

Sift4G

Uncertain

0.014

Polyphen

0.029

Vest4

0.17

MutPred

0.50

Loss of disorder (P = 0.0849)

MVP

0.59

ClinPred

1.0

GERP RS

4.9

Varity_R

0.15

gMVP

0.49

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.69

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over