rs41281316

Variant names:

• chr10-71730553-G-A
• rs41281316
• NM_022124.6:c.3664G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71730553-G-A
• chr10-71730553-G-T

Variant summary

Our verdict is Benign. The variant received -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. 11/18 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:12
• Conservation: PhyloP100: 6.61
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 45927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3664G>A	p.Ala1222Thr	missense_variant	Exon 31 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.3664G>A	p.Ala1222Thr	missense_variant	Exon 31 of 32		NP_001165401.1
C10orf105	NM_001168390.2	c.-6+7175C>T		intron_variant	Intron 1 of 1		NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3664G>A	p.Ala1222Thr	missense_variant	Exon 31 of 70	5	NM_022124.6	ENSP00000224721.9

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

GnomAD2 exomes AF: 0.0208 AC: 5187 AN: 248828 AF XY: 0.0217

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 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

African (AFR) AF: 0.00454 AC: 152 AN: 33480

American (AMR) AF: 0.0134 AC: 598 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 1433 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0128 AC: 1104 AN: 86234

European-Finnish (FIN) AF: 0.0194 AC: 1033 AN: 53352

Middle Eastern (MID) AF: 0.0348 AC: 200 AN: 5742

European-Non Finnish (NFE) AF: 0.0286 AC: 31810 AN: 1111836

Other (OTH) AF: 0.0270 AC: 1630 AN: 60366

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

African (AFR) AF: 0.00568 AC: 236 AN: 41574

American (AMR) AF: 0.0277 AC: 424 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4834

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0282 AC: 1917 AN: 68026

Other (OTH) AF: 0.0317 AC: 67 AN: 2116

Alfa AF: 0.0265 Hom.: 196

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Oct 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:3

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Usher syndrome type 1D Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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
MutationAssessor	Benign	0.82	.;.;L;.
PhyloP100		6.6
PrimateAI	Uncertain	0.61	T
REVEL	Benign	0.18
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
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

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