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 (★★). The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• 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:13
• 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

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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,Unknown gene

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.3664G>A	p.Ala1222Thr	missense	Exon 31 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3664G>A	p.Ala1222Thr	missense	Exon 31 of 32	NP_001165401.1	A0A087WYR8
	C10orf105	NM_001168390.2		c.-6+7175C>T		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.3664G>A	p.Ala1222Thr	missense	Exon 31 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.3664G>A	p.Ala1222Thr	missense	Exon 31 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.3661G>A	p.Ala1221Thr	missense	Exon 31 of 32	ENSP00000381789.5	A0A0A0MS94

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0072	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
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;