10-71712805-A-T

Position:

• chr10-71712805-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_022124.6(CDH23):​c.3361A>T​(p.Ile1121Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,612,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 6.27

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]

CDH23 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a domain Cadherin 11 (size 105) in uniprot entity CAD23_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_022124.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.013111502).
• BP6: Variant 10-71712805-A-T is Benign according to our data. Variant chr10-71712805-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45916.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3361A>T	p.Ile1121Phe	missense_variant	28/70	ENST00000224721.12	NP_071407.4
C10orf105	NM_001164375.3	c.*3131T>A		3_prime_UTR_variant	2/2	ENST00000441508.4	NP_001157847.1
CDH23	NM_001171930.2	c.3361A>T	p.Ile1121Phe	missense_variant	28/32		NP_001165401.1
C10orf105	NM_001168390.2	c.*3131T>A		3_prime_UTR_variant	2/2		NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3361A>T	p.Ile1121Phe	missense_variant	28/70	5	NM_022124.6	ENSP00000224721.9
C10orf105	ENST00000441508.4	c.*3131T>A		3_prime_UTR_variant	2/2	1	NM_001164375.3	ENSP00000403151.2

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000332 AC: 81 AN: 243680 Hom.: 0 AF XY: 0.000218 AC XY: 29 AN XY: 132766

Gnomad AFR exome AF: 0.00494

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1459744 Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 725998

Gnomad4 AFR exome AF: 0.00445

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74522

Gnomad4 AFR AF: 0.00450

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.00151

ESP6500AA AF: 0.00416 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 48

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2017	The p.Ile1121Phe variant (rs200542052) has not been reported in the medical literature. This variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.46% in the African population (identified in 108 out of 23,580 chromosomes; 0 homozygotes), and is listed in ClinVar with conflicting interpretations of pathogenicity (benign/uncertain significance; Variant ID: 45916). The isoleucine at codon 1121 is highly conserved considering 12 species up to zebrafish (Alamut software v2.9.0), and computational analyses suggest that this variant affects the CDH23 protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). While the frequency of this variant in the African population suggests that it is a benign polymorphism, the available evidence is insufficient to classify the clinical significance with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2020	- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 20, 2018

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 02, 2015

p.Ile1121Phe in exon 28 of CDH23: This variant is not expected to have clinical significance because it is has been identified in 0.6% (44/7874) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs200542052). -

Usher syndrome type 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D;D;D;D;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.7	.;.;L;.;.
PrimateAI	Uncertain	0.52	T
REVEL	Uncertain	0.31
Sift4G	Uncertain	0.0030	D;D;.;D;.
Polyphen		0.85	.;.;P;.;.
Vest4		0.93
MVP		0.88
ClinPred		0.092	T
GERP RS		4.9
Varity_R		0.34
gMVP		0.73

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: rs200542052; hg19: chr10-73472562;