rs111033453

Variant names:

• chr10-71732270-G-A
• rs111033453
• NM_022124.6:c.3999G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71732270-G-A
• chr10-71732270-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.3999G>A​(p.Val1333Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,613,534 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1333V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.48
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-71732270-G-A is Benign according to our data. Variant chr10-71732270-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45935.
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00289 (440/152306) while in subpopulation NFE AF = 0.0034 (231/68026). AF 95% confidence interval is 0.00304. There are 1 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.3999G>A	p.Val1333Val	synonymous	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3999G>A	p.Val1333Val	synonymous	Exon 32 of 32	NP_001165401.1
	C10orf105	NM_001168390.2		c.-6+5458C>T		intron	N/A	NP_001161862.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3999G>A	p.Val1333Val	synonymous	Exon 32 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.3999G>A	p.Val1333Val	synonymous	Exon 32 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.3996G>A	p.Val1332Val	synonymous	Exon 32 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00310 AC: 769 AN: 247904 AF XY: 0.00314

Gnomad AFR exome AF: 0.000393

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00549

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00940

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00264 AC: 3861 AN: 1461228 Hom.: 11 Cov.: 31 AF XY: 0.00269 AC XY: 1958 AN XY: 726842

African (AFR) AF: 0.000747 AC: 25 AN: 33470

American (AMR) AF: 0.00204 AC: 91 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 127 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000847 AC: 73 AN: 86144

European-Finnish (FIN) AF: 0.00907 AC: 484 AN: 53370

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5766

European-Non Finnish (NFE) AF: 0.00257 AC: 2859 AN: 1111648

Other (OTH) AF: 0.00285 AC: 172 AN: 60360

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74480

African (AFR) AF: 0.000505 AC: 21 AN: 41558

American (AMR) AF: 0.00281 AC: 43 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00340 AC: 231 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00329 Hom.: 1

Bravo AF: 0.00214

EpiCase AF: 0.00371

EpiControl AF: 0.00333

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.1
DANN	Benign	0.83
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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: rs111033453; hg19: chr10-73492027;