rs41281314

Variant names:

• chr10-71730514-A-G
• rs41281314
• NM_022124.6:c.3625A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BA1 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 3442/23972) of the c.3625A>G (p.Thr1209Ala) variant in the CDH23 gene is 13.15% for African chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). A splicing assay did not show any impact to splicing but BS3 was not applied given no assessment of protein function (PMID:18273900). Computational prediction analysis using the metapredictor tool REVEL did not predict an impact the protein (BP4). Of note, this variant was reported in 3 patients with Usher syndrome (PMID:15537665, 15660226, 12075507) though without any convincing evidence for pathogenicity (PM3 not met). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BS3_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA137387/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.042 (462 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (444 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:13 O:2
• Conservation: PhyloP100: 6.15
• Publications: 17 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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.3625A>G	p.Thr1209Ala	missense	Exon 31 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3625A>G	p.Thr1209Ala	missense	Exon 31 of 32	NP_001165401.1	A0A087WYR8
	C10orf105	NM_001168390.2		c.-6+7214T>C		intron	N/A	NP_001161862.1	Q8TEF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3625A>G	p.Thr1209Ala	missense	Exon 31 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.3625A>G	p.Thr1209Ala	missense	Exon 31 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.3622A>G	p.Thr1208Ala	missense	Exon 31 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 6466 AN: 152180 Hom.: 463 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0105 AC: 2625 AN: 249000 AF XY: 0.00785

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00768

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.000629

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00440 AC: 6438 AN: 1461618 Hom.: 444 Cov.: 31 AF XY: 0.00376 AC XY: 2731 AN XY: 727086

African (AFR) AF: 0.150 AC: 5032 AN: 33478

American (AMR) AF: 0.00894 AC: 400 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86250

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53390

Middle Eastern (MID) AF: 0.00680 AC: 39 AN: 5734

European-Non Finnish (NFE) AF: 0.000307 AC: 341 AN: 1111848

Other (OTH) AF: 0.00982 AC: 593 AN: 60364

GnomAD4 genome AF: 0.0425 AC: 6472 AN: 152298 Hom.: 462 Cov.: 33 AF XY: 0.0407 AC XY: 3033 AN XY: 74470

African (AFR) AF: 0.146 AC: 6061 AN: 41536

American (AMR) AF: 0.0193 AC: 295 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68032

Other (OTH) AF: 0.0321 AC: 68 AN: 2116

Alfa AF: 0.0180 Hom.: 385

Bravo AF: 0.0489

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.142 AC: 574

ESP6500EA AF: 0.000599 AC: 5

ExAC AF: 0.0128 AC: 1553

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (5)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types (1)
-	-	1	Usher syndrome (1)
-	-	1	Usher syndrome type 1 (2)
-	1	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.60	N
PhyloP100		6.2
PrimateAI	Uncertain	0.61	T
REVEL	Benign	0.28
Sift4G	Uncertain	0.014	D
Polyphen		0.57	P
Vest4		0.47
ClinPred		0.038	T
GERP RS		3.2
Varity_R		0.18
gMVP		0.36
Mutation Taster		=84/16	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: rs41281314; hg19: chr10-73490271; COSMIC: COSV56497382;