rs727504705

chr10-71712770-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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. 11/19 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.3326C>T	p.Ala1109Val	missense_variant	28/70	ENST00000224721.12
C10orf105	NM_001164375.3	c.*3166G>A		3_prime_UTR_variant	2/2	ENST00000441508.4
CDH23	NM_001171930.2	c.3326C>T	p.Ala1109Val	missense_variant	28/32
C10orf105	NM_001168390.2	c.*3166G>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3326C>T	p.Ala1109Val	missense_variant	28/70	5	NM_022124.6	P1
C10orf105	ENST00000441508.4	c.*3166G>A		3_prime_UTR_variant	2/2	1	NM_001164375.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 07, 2013

Variant classified as Uncertain Significance - Favor Benign. The Ala1109Val vari ant in CDH23 has not been reported in individuals with hearing loss or in large population studies. Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala1109Val variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Of note, zebra finch and lamprey have a valine (Val) at this position despite high nearby amino acid conservation. In summary, the clin ical significance of this variant cannot be determined with certainty; however, based upon the conservation and computational data, we lean towards a more likel y benign role. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Benign	0.94
DEOGEN2	Benign	0.0022	T;T;T;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.42	T
Sift4G	Uncertain	0.014	D;T;.;D;.
Polyphen		0.029	.;.;B;.;.
Vest4		0.17
MutPred		0.50		Loss of disorder (P = 0.0849);Loss of disorder (P = 0.0849);Loss of disorder (P = 0.0849);Loss of disorder (P = 0.0849);Loss of disorder (P = 0.0849);
MVP		0.59
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.15
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs727504705; hg19: chr10-73472527;