rs41281316

Positions:

• chr10-71730553-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022124.6(CDH23):​c.3664G>A​(p.Ala1222Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0254 in 1,613,902 control chromosomes in the GnomAD database, including 621 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (44 hom., cov: 33)
  • Exomes 𝑓: 0.026 (577 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.61

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007181257).
• BP6: Variant 10-71730553-G-A is Benign according to our data. Variant chr10-71730553-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71730553-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0203 (3096/152342) while in subpopulation NFE AF= 0.0282 (1917/68026). AF 95% confidence interval is 0.0271. There are 44 homozygotes in gnomad4. There are 1503 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.3664G>A	p.Ala1222Thr	missense_variant	31/70	ENST00000224721.12
CDH23	NM_001171930.2	c.3664G>A	p.Ala1222Thr	missense_variant	31/32
C10orf105	NM_001168390.2	c.-6+7175C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3664G>A	p.Ala1222Thr	missense_variant	31/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3098 AN: 152224 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.00569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0282

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0208 AC: 5187 AN: 248828 Hom.: 75 AF XY: 0.0217 AC XY: 2935 AN XY: 135078

Gnomad AFR exome AF: 0.00434

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0126

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0291

GnomAD4 exome AF: 0.0260 AC: 37965 AN: 1461560 Hom.: 577 Cov.: 31 AF XY: 0.0258 AC XY: 18790 AN XY: 727068

Gnomad4 AFR exome AF: 0.00454

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.0548

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0286

Gnomad4 OTH exome AF: 0.0270

GnomAD4 genome AF: 0.0203 AC: 3096 AN: 152342 Hom.: 44 Cov.: 33 AF XY: 0.0202 AC XY: 1503 AN XY: 74484

Gnomad4 AFR AF: 0.00568

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0199

Gnomad4 NFE AF: 0.0282

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0273 Hom.: 106

Bravo AF: 0.0210

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.00542 AC: 22

ESP6500EA AF: 0.0334 AC: 280

ExAC AF: 0.0207 AC: 2503

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0312

EpiControl AF: 0.0308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T;T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T;T;T
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
Sift4G	Uncertain	0.028	D;D;.;D
Polyphen		0.89	.;.;P;.
Vest4		0.58
ClinPred		0.039	T
GERP RS		3.4
Varity_R		0.099
gMVP		0.39

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: rs41281316; hg19: chr10-73490310; COSMIC: COSV56478314;